KR20220011673A - Pyridinone derivatives as selective cytotoxic agents for HIV-infected cells - Google Patents

Abstract

The present disclosure relates to pyridinone derivatives of formula (I) and their use for selectively killing HIV infected GAG-POL expressing cells without cytotoxicity to HIV naive cells, and for the treatment of infection by HIV, or AIDS or to its use for treating, preventing or delaying the onset or progression of AIDS-related complications (ARC).

Description

Pyridinone derivatives as selective cytotoxic agents for HIV-infected cells

Human immunodeficiency virus (HIV) is the pathogen of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, HIV-infected humans develop severe immunodeficiency, which renders them highly susceptible to debilitating and ultimately fatal opportunistic infections. A number of clinically approved antiretroviral drugs are available that demonstrate multi-log reductions in viral load. Treated patients are at risk of acquiring mutations that render their viruses resistant to available therapies, and a rapid rebound of viremia is observed when therapy is removed, indicating that current therapies are not curative.

HIV is a retrovirus, whose life cycle involves the reverse transcription of the viral RNA genome into DNA via an enzyme known as reverse transcriptase and subsequent integration of the DNA copy into the host chromosomal DNA via an integrase encoded by the virus. it entails Viral RNA is transcribed, and viral proteins are translated using the host cell machinery along with viral helper proteins. Many viral proteins are contained within the GAG and GAG-POL proteins, where the GAG-containing structural proteins and GAG-POL are generated from a frameshift near the carboxy-terminus of the GAG, in addition to the structural proteins protease (PR), reverse transcription Contains tase (RT) and integrase (IN) viral enzymes. GAG and GAG-POL are cleaved into individual proteins through a maturation process that occurs during extrusion of virions from infected cells. At this time, GAG-POL dimerizes and HIV PR, the current dimer within the GAG-POL dimer, forms an active enzyme, which cleaves itself from the polyprotein and catalyzes further cleavage to catalyze the remaining viral enzymes and structural proteins. can form.

Available antiretroviral drugs act by blocking the virus at different stages of the viral life cycle. For example, reverse transcriptase inhibitors target viral reverse transcriptase to prevent the RNA genome from being copied into DNA, integrase inhibitors block the ability of the copied DNA to integrate into host cells, and protease inhibitors prevents viral maturation, leaving virions produced from cells treated with protease inhibitors immature and non-infectious. Once integration occurs, cells are infected until death via the normal apoptosis pathway, or accelerated death due to viral factors, or targeted by the immune system. Although most infected cells are expected to die within ∼2 days of infection, the rapid rebound of viremia when therapy is removed indicates that infected cells remain many years after receiving therapy (see, e.g., JB Dinoso et al. al., Proc. Natl. Acad. Sci. USA, 2009, 106(23): 9403-9408). Therefore, new therapies that can selectively kill HIV-infected cells will provide new treatment options for HIV infection. Treatment with compounds capable of accelerating the death of HIV-infected cells and reducing the overall number of persistent virus-infected cells in a patient has the potential to reduce low-level viremia in suppressed patients, and is also an important factor in HIV treatment strategies. It may play a certain role.

The present disclosure relates to pyridinone derivatives and their use as small molecule activated cell death (SMACK) agonists that accelerate the death of HIV GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells. Accordingly, the compounds disclosed herein are useful for the treatment of infection by HIV, or for the treatment, prevention or delay of the onset or progression of AIDS or AIDS-related complications (ARC). Additionally, the compounds are useful for selectively killing HIV-infected GAG-POL expressing cells in an HIV-infected subject. Compositions and methods of use comprising the compounds of the present disclosure are also provided.

The present disclosure relates to pyridinone derivative compounds and their use for accelerating the death of HIV GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells. In the absence of compounds such as those from the present invention, PR activation occurs during viral maturation and the concentration of mature PR in the cytoplasm is limited. In contrast, compounds of the present invention promote the desired phenotype by binding to the immature RT binding site and catalyzing GAG-POL dimerization inside infected cells by triggering early activation of the HIV PR enzyme inside the host infected cells prior to extrusion. As a result, PR cleaves the host matrix within the cell, inducing cytotoxicity and cell death. This effect can be blocked in the presence of an HIV protease inhibitor such as indinavir or darunavir, demonstrating a role for the HIV protease in the process.

The compounds disclosed herein are also non-nucleoside reverse trans, because homology between the mature and immature RT pockets in HIV allows the compounds to bind to the mature hydrophobic pocket near the active site of the viral RT enzyme. It has activity as a cryptase inhibitor (NNRTI). Binding to mature RT leads to inhibition of enzymatic activity and production of DNA provirus, which prevents infection of naive CD4+ T-cells.

The effect of NNRTIs on dimerization of RT and GAG-POL has been documented (Tachedjian et al. Proc. Natl. Acad. Sci. USA 2001, 98(13):7188; Tachedjian et al. FEBS Lett. 2005, 579). :379; Figueiredo et al. PLOS Path. 2006, 2(11):1051; Sudo et al. J. Virol. 2013, 87(6):3348), selective killing of HIV-infected cells as a result of enhanced dimerization was first reported by Jochmans et al. (Jochmans et al. Retrovirology 2010, 7:89). The authors generated data demonstrating these effects in chronically infected MT-4 cells, PBMCs and CD4+ cells. Based on the potency of the tested molecules, they concluded: "These data present a proof-of-concept for targeted drug-induced clearance of HIV-producing cells. NNRTIs by themselves may not be robust enough for therapeutic use. However, the results provide a basis for the development of drugs that exploit this mechanism of action." More recently, Zerbato et al. (Zerbato et al. Antimicrob. Agents Chemother. 2017, 61(3)) measured the activity of NNRTIs in a primary cell model for HIV latency. They observed a significant decrease in virus production for certain NNRTIs compared to other classes of antiretroviral agents, inferred to be due to the ability of these compounds to eliminate cells expressing the HIV GAG-POL protein.

The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

here

R ¹ is H, halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or substituted with 1 to 7 F -C _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F;

R ² is CN and R ³ is H; or R ² is H and R ³ is CN;

R ⁴ is -H, halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or substituted with 1 to 7 F -C _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F;

R ⁵ is -H, halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or substituted with 1-7 F -C _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F;

R ⁶ _{is halo or —C 1-6} alkyl substituted with 1 to 9 —F;

R ⁷ is —H or —C _1-3 alkyl;

R ⁸ is -H, halo or -C _1-3 alkyl;

R ⁹ is —H, pyrazolyl, or —C _1-6 alkyl unsubstituted or substituted with —OH or —OC _{1-3 alkyl.}

In embodiment 1 of the present disclosure, ^{is a compound of formula (I) having structural formula (II), wherein R 2} is CN and R ³ is H: or a pharmaceutically acceptable salt thereof:

wherein R ¹ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined in formula (I).

In embodiment 2 of the present disclosure,

R ⁴ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, —C unsubstituted or substituted with 1 to 7 F _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F

a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt of each of the foregoing. In class 1 thereof, R ⁴ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. In his class 2, R ⁴ is a -CH ₃ substituted by halo, -CH _3, or one to three F.

In embodiment 3A of the present disclosure, R ¹ is a compound of Formula I, Formula II, Embodiment 2, or any class thereof, wherein R 1 is H, or a pharmaceutically acceptable salt of each of the foregoing.

In embodiment 3B of the disclosure, R ¹ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, unsubstituted or 1 _{-C 1-3} alkyl substituted with to 7 F _{, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F; , or a pharmaceutically acceptable salt of each of the foregoing. In class 1 thereof, R ¹ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. In class 2 thereof, R ¹ is halo or CH ₃ .

In embodiment 4 of the present disclosure, ^{is a compound of Formula I, having structural formula III, wherein R 2} is H and R ³ is CN, or a pharmaceutically acceptable salt thereof:

wherein R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined in formula (I).

In embodiment 5A of the present disclosure,

R ¹ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, —C unsubstituted or substituted with 1 to 7 F _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F

a compound of formula (I) or formula (III), or a pharmaceutically acceptable salt of each of the foregoing. In class 1 thereof, R ¹ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. In class 2 thereof, R ¹ is halo or CH ₃ .

In embodiment 5B of the present disclosure,

R ⁵ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, —C unsubstituted or substituted with 1 to 7 F _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F

a compound of formula (I) or formula (III), or a pharmaceutically acceptable salt of each of the foregoing. In class 1 thereof, R ⁵ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. In his class 2, R ⁵ is a -CH ₃ substituted by halo, -CH _3, or one to three F.

In embodiment 6 of the present disclosure, R ⁶ _{is —C 1-4} alkyl substituted with halo, or 1 to 9 —F, Formula I, Formula II, Formula III, or Embodiments 2, 3A, 3B, 5A or 5B, or a compound of any class thereof, or a pharmaceutically acceptable salt of each of the foregoing. In class 1 thereof, R ⁶ _{is halo, or —C 1-3} alkyl substituted with 1 to 7 —F. In class 2 thereof, R ⁶ _{is halo, or —C 1-2} alkyl substituted with 1 to 5 —F.

In embodiment 7 of the present disclosure, R ⁷ is H or —CH ₃ , or a compound of Formula I, Formula II, Formula III, or Embodiments 2, 3A, 3B, 5A, 5B or 6, or any class thereof, or a pharmaceutically acceptable salt of each of the foregoing.

In embodiment 8 of the present disclosure, R ⁸ is -H or halo; or a pharmaceutically acceptable salt of each of the foregoing.

In embodiment 9 of the present disclosure, R ⁹ is —H, pyrazolyl, or —C _1-4 alkyl unsubstituted or substituted with —OH or —OC _{1-3 alkyl;} embodiment 2, 3A, 3B, 5A, 5B, 6, 7 or 8, or a compound of any class thereof, or a pharmaceutically acceptable salt of each of the foregoing. In class 1 thereof, R ⁹ is —H, pyrazolyl, or —C _1-3 alkyl unsubstituted or substituted with —OH or —OC _{1-3 alkyl.} In class 2 thereof, R ⁹ is —H, pyrazolyl, or _{—C 1-3} alkyl unsubstituted or substituted with _{—OH or —OCH 3 .}

In embodiment 10 of the present disclosure,

R ¹ _{is H, halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F; for example R ¹ is H, halo or CH ₃ ;

R ⁴ is halo, -CH _3, or one to three F a -CH ₃ optionally substituted with a;

R ⁶ _{is halo or —C 1-3} alkyl substituted with 1 to 7 —F, eg R ⁶ _{is —C 1-2} alkyl substituted with 1 to 5 —F;

R ⁷ is —H or —C _1-3 alkyl, eg R ⁷ is H or —CH ₃ ;

R ⁸ is -H, halo or -C _1-3 alkyl, eg R ⁸ is -H or halo;

R ⁹ _{is —H, pyrazolyl, or —C 1-6} alkyl unsubstituted or substituted with —OH or —OC _1-3 alkyl, for example R ⁹ is —H, pyrazolyl, or unsubstituted or — _{-C 1-3} alkyl substituted with OH or -OCH ₃

a compound of formula I or II, or a pharmaceutically acceptable salt thereof.

In embodiment 11 of the present disclosure,

R ¹ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F, eg R ¹ is halo or CH ₃ ;

R ⁵ is halo, or is unsubstituted or substituted with -C _1-3 alkyl substituted with 1 to 7 F, for example, R ⁵ is a -CH ₃ substituted with halo, -CH _3, or one to three F, for example R ⁵ is —CH ₃ ;

R ⁶ _{is halo or —C 1-3} alkyl substituted with 1 to 7 —F, eg R ⁶ _{is —C 1-2} alkyl substituted with 1 to 5 —F;

R ⁷ is —H or —C _1-3 alkyl, eg R ⁷ is H or —CH ₃ ;

R ⁸ is -H, halo or -C _1-3 alkyl, eg R ⁸ is -H or halo;

R ⁹ _{is —H, pyrazolyl, or —C 1-6} alkyl unsubstituted or substituted with —OH or —OC _1-3 alkyl, for example R ⁹ is —H, pyrazolyl, or unsubstituted or — _{-C 1-3} alkyl substituted with OH or -OCH ₃

It is a compound of formula (I) or (III) or a pharmaceutically acceptable salt thereof.

Reference herein to compounds of formula (I) encompasses compounds of formulas (I), (II) and (III) and embodiments and classes thereof. The compounds of formula (I) may be in the form of neutral compounds or salts (where such salts are possible), such as pharmaceutically acceptable salts.

The term "for example (e.g.)" means "for example." Where the terms “eg” or “for example” are used herein, the recited example(s) is intended to be illustrative, and is not intended to be an exhaustive list of all relevant examples. does not

As used herein, “alkyl” refers to both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms within the specified range. For example, the term “C _1-6 alkyl” refers to a linear or branched chain alkyl group, including all possible isomers having 1, 2, 3, 4, 5 or 6 carbon atoms, the hexyl and pentyl isomers respectively as well as n-, iso-, sec- and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively “C ₄ alkyl”; Bu = butyl), n- and iso-propyl ( propyl, i-propyl, collectively "C ₃ alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). “C _1-4 alkyl” has 1, 2, 3 or 4 carbon atoms and includes n-, i-, s- and t-butyl, n- and i-propyl, ethyl and methyl respectively. “C _1-3 alkyl” has 1, 2 or 3 carbon atoms and includes each of n-propyl, i-propyl, ethyl and methyl.

“Cycloalkyl” refers to a cyclized alkyl ring having the indicated number of carbon atoms within the specified range. Thus, for example, "C _3-6 cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and "C _3-4 cycloalkyl" includes each of cyclopropyl and cyclobutyl. .

“Halo” or “halogen” refers to chloro, fluoro, bromo or iodo. Chloro, fluoro and bromo are classes of halogens of interest, more particularly chloro and fluoro.

An “HIV naive cell(s)” is a cell that is not infected with HIV.

A “compatible anti-HIV agent(s)” is an anti-HIV agent, other than an HIV protease inhibitor.

A “stable” compound is one that can be prepared and isolated and whose structure and properties are essential for a period of time sufficient to permit use of the compound for the purposes described herein (eg, therapeutic or prophylactic administration to a subject). It is a compound that can be maintained or can be maintained without changing to. Compounds of the present disclosure are limited to stable compounds encompassed by Formula I and embodiments thereof. For example, certain moieties as defined in formula (I) may be unsubstituted or substituted, the latter encompassing substitution patterns (i.e. number and type of substituents) that result in chemically capable and stable compounds for the moiety. it is intended to

The present disclosure includes the individual diastereomers, particularly epimers, i.e. compounds having the same chemical formula but differing in the spatial arrangement around a single atom. The present disclosure also includes mixtures of diastereomers in all ratios, especially mixtures of epimers. The present disclosure encompasses compounds of formula (I) having asymmetric centers and compounds of formula (I) as well as (R) or (S) stereo-configurations at any additional asymmetric centers that may be present in stereo-isomeric mixtures thereof. Embodiments of the present disclosure also include mixtures of enantiomers enriched in at least 51% of one enantiomer, including, for example, at least 60%, at least 70%, at least 80%, or at least 90% of the one enantiomer. include A single epimer is preferred. Individual or single enantiomers refer to enantiomers obtained by chiral synthesis and/or using generally known separation and purification techniques, which may be 100% of one enantiomer or may be in small amounts (e.g. , 10% or less) of opposite enantiomers. Accordingly, individual enantiomers are the subject of the present disclosure in pure form as both levorotatory and dextrotropic antipodes, in racemic form and in the form of mixtures of the two enantiomers in all ratios. In the case of cis/trans isomerism, the present disclosure includes both the cis and trans forms, as well as mixtures of these forms in all ratios.

The preparation of the individual stereoisomers can, if desired, be carried out by customary methods, for example, separation of the mixture by chromatography or crystallization, the use of stereochemically homogeneous starting materials for the synthesis or by stereoselective synthesis. . Optionally, derivatization may be performed prior to separation of stereoisomers. Separation of mixtures of stereoisomers can be carried out at intermediate steps during the synthesis of the compounds of formula (I) or can be carried out on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of derivatized crystalline products or crystalline intermediates, if necessary, using reagents containing stereogenic centers of known coordination. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy analysis. This disclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers, and mixtures thereof.

As will be appreciated by one of ordinary skill in the art, certain compounds of the present disclosure may exist as tautomers. All tautomeric forms of these compounds, whether isolated individually or in mixtures, are within the scope of this disclosure. For example, where an oxo (=O) substituent is allowed on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent may exist in fact in whole or in part in the -OH form.

Atoms in a compound of formula (I) may exhibit their natural isotopic abundance, or certain isotopes in which one or more of the atoms have the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature The element may be artificially enriched. This disclosure is intended to cover all suitable isotopic variations of the compounds of formula (I); For example, different isotopic forms of hydrogen ( ^{H) include light hydrogen ( 1} H) and deuterium ( ² H). Light hydrogen is the predominant hydrogen isotope found in nature. Deuterium enrichment may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. Isotopically-enriched compounds of formula (I) can be prepared by conventional techniques well known to those skilled in the art using appropriate isotopically-enriched reagents and/or intermediates or by methods analogous to those described in the schemes and examples herein. can be prepared without excessive experimentation.

The compounds may be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to a salt that retains the effectiveness of the parent compound and is not biologically or otherwise undesirable (eg, neither toxic nor otherwise harmful to its recipient). When the compound of formula (I) contains at least one acidic or basic group, the present invention includes the corresponding pharmaceutically acceptable salts.

Thus, compounds of formula (I) containing acidic groups (eg -COOH) can be used according to the invention, for example, but without limitation, as alkali metal salts, alkaline earth metal salts or ammonium salts. Examples of such salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula (I) containing at least one basic group, i.e. a group capable of being protonated, are in accordance with the invention in the form of their acid addition salts with inorganic or organic acids, including but not limited to hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid , nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid , pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and the like. If the compounds of formula (I) simultaneously contain acidic and basic groups in the molecule, the present invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). Salts can be prepared by conventional methods known to the person skilled in the art, for example by combination with organic or inorganic acids or bases in solvents or dispersants, or by anion exchange or cation exchange from other salts. It can be obtained from the compound of I. The present invention also includes all salts of the compounds of formula (I) which are not directly suitable for use in pharmaceuticals due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. do.

The present disclosure includes, but is not limited to, compositions comprising, for example, but not limited to, such compounds (which may be referred to as "co-crystals") in association with one or more additional molecular and/or ionic component(s); Any composition consisting of a compound that is a compound of formula (I) or a salt thereof is encompassed. As used herein, the term “co-crystal” refers to a solid phase (which may or may not be crystalline) wherein two or more different molecular and/or ionic components (generally in stoichiometric ratios) are hydrogen-bonded; held together by non-ionic interactions including, but not limited to, dipole-dipole interactions, dipole-tetrapole interactions, or dispersive forces (van der Waals). There is no transfer of protons between dissimilar components, and the solid phase is neither a simple salt nor a solvate. A discussion of co-crystals can be found, for example, in S. Aitipamula et al., Crystal Growth and Design, 2012, 12 (5), pp. 2147-2152].

Additionally, the compounds of the present disclosure may exist in amorphous and/or one or more crystalline forms, and all such amorphous and crystalline forms of the compound of formula (I) and salts thereof and mixtures thereof are intended to be included within the scope of this disclosure. It is intended Additionally, some of the compounds of the present disclosure may form solvates (ie, hydrates) with water or solvates with common organic solvents. Such solvates and hydrates of the compounds of the present disclosure, in particular pharmaceutically acceptable solvates and hydrates, are likewise within the scope of the compounds defined by formula (I) and pharmaceutically acceptable salts thereof, the non-solvated and anhydrous forms of such compounds. is covered with

Accordingly, a compound of Formula (I) or a salt thereof, including a pharmaceutically acceptable salt thereof, and embodiments thereof, and the specific compounds described and claimed herein, are in all possible stereoisomers, tautomers, physical forms (e.g., amorphous and crystalline forms). ), co-crystal forms, solvate and hydrate forms, and any combination of the above forms where such forms are possible.

Another embodiment of the present disclosure is a compound of Formula (I), wherein the compound or salt thereof is in substantially pure form. As used herein, "substantially pure" is suitably at least about 60% by weight of a product containing a compound of formula (I) or a salt thereof (e.g., a product isolated from a reaction mixture to provide the compound or salt), typically at least about 70 wt%, preferably at least about 80 wt%, more preferably at least about 90 wt% (e.g., about 90 wt% to about 99 wt%), even more preferably at least about 95 wt% % (e.g., from about 95 wt% to about 99 wt% or from about 98 wt% to 100 wt%), and most preferably at least about 99 wt% (e.g., 100 wt%) to the compound or salt it means done The purity levels of compounds and salts can be determined using standard analytical methods such as high performance liquid chromatography and/or mass spectrometry or NMR techniques. If more than one analytical method is used and the method provides an experimentally significant difference in the determined level of purity, the method providing the highest level of purity takes precedence. A compound or salt of 100% purity is free of detectable impurities as determined by standard analytical methods. With respect to compounds of the present invention which have one or more centers of asymmetry and may occur as mixtures of stereoisomers, a substantially pure compound may be a substantially pure mixture of stereoisomers or a substantially pure individual stereoisomer.

The compounds of formula (I) herein and their pharmaceutically acceptable salts elicit GAG-POL dimerization in HIV-infected cells, thereby killing HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells. It is useful for selectively killing, which is referred to herein as small molecule activated cell death (SMACK) activity. Accordingly, compounds of formula (I) and pharmaceutically acceptable salts thereof are useful for:

(i) comprising administering to a human subject in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of infection by HIV, or for the treatment, prevention or delay of the onset or progression of AIDS or ARC. a method for treating or preventing infection by HIV, or for treating, preventing, or delaying the onset or progression of AIDS or ARC in said human subject;

(ii) HIV in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof - a method of eliciting GAG-POL dimerization in infected cells; and/or

(iii) HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells in a human subject, comprising administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof How to selectively kill

Additionally, the compound of formula (I) and pharmaceutically acceptable salts thereof can be administered to a human subject in an effective amount of a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor, a non-nucleoside HIV reverse transcriptase. The method (i), (ii) and (iii) above further comprising administering at least one compatible HIV antiviral agent selected from an antase inhibitor, an HIV integrase inhibitor, an HIV fusion inhibitor, an HIV entry inhibitor and an HIV maturation inhibitor. It is useful for any of the methods. In the method of (i), (ii) or (iii) immediately above, the human subject is treated with a compound of Formula I, or a pharmaceutically acceptable salt thereof, in addition to treatment with one or more compatible HIV antiviral agents.

The compound of formula (I) and a pharmaceutically acceptable salt thereof may also contain an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents. It is useful in a method of enhancing the inhibition of HIV viremia in said human subject comprising additionally administering.

Other embodiments of the present disclosure include:

(a) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(b) a pharmaceutical composition comprising a product prepared by combining (eg, admixing) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(c) the pharmaceutical composition of (a) or (b) further comprising an effective amount of at least one compatible anti-HIV agent selected from the group consisting of an HIV antiviral agent, an immunomodulatory agent and an anti-infective agent.

(d) the compatible anti-HIV agent is a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a nucleoside HIV reverse transcriptase translocation inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, an HIV integrase inhibitor; The pharmaceutical composition of (c), wherein the pharmaceutical composition is selected from one or more of an antiviral agent selected from the group consisting of HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.

(e) a combination that is (i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (ii) at least one compatible anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators and anti-infective agents; wherein the compound and the compatible anti-HIV agent are each used in an amount such that the combination is effective in the treatment of infection by HIV, or in the treatment, prevention, or delay of the onset or progression of AIDS or ARC.

(f) the compatible anti-HIV agent is a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, HIV The combination of (e) which is an antiviral agent selected from the group consisting of a fusion inhibitor, an HIV entry inhibitor and an HIV maturation inhibitor.

(g) a method of eliciting GAG-POL dimerization in HIV-infected cells, a method of selectively killing HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells, and/or in need of treatment A method of treating infection by HIV, or treating, preventing, or delaying the onset or progression of AIDS or ARC, comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

(h) the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an effective amount of a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor , an HIV integrase inhibitor, an HIV fusion inhibitor, an HIV entry inhibitor and an HIV maturation inhibitor in combination with at least one other compatible HIV antiviral agent.

The method of (g) or (h) comprising (i) administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or a combination of (e) or (f).

(j) (1) elicit GAG-POL dimerization in HIV-infected cells in the subject; (2) selectively killing HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells in the subject; (3) treating infection by HIV in a subject; (4) treating, preventing or delaying the onset or progression of AIDS or ARC in a subject; (5) Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for enhancing the inhibition of HIV viremia in a subject receiving treatment with a compatible anti-HIV agent.

(k) (1) elicit GAG-POL dimerization in HIV-infected cells; (2) selectively killing HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells; (3) treat infection by HIV; (4) treat, prevent or delay the onset or progression of AIDS or ARC; (5) A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in enhancing the inhibition of HIV viremia in a subject receiving treatment with a compatible anti-HIV agent.

A further embodiment of the present invention encompasses each of the pharmaceutical compositions, methods and uses set forth in the paragraphs above, wherein the compound of formula (I) or a salt thereof is employed substantially pure therein. With respect to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and a pharmaceutically acceptable carrier and optionally one or more excipients, the term "substantially pure" is understood to relate to the compound of formula I or a salt thereof per se.

Another embodiment of the present disclosure is the pharmaceutical compositions, methods and uses set forth above, wherein the HIV of interest is HIV-1.

The term "administration" and variants thereof (eg, "administering" the compound) with respect to a compound of formula (I) means providing the compound to a subject in need of treatment or prophylaxis, self-administration and another including both administration to a patient by a human. When a compound is provided in combination with one or more other active agents (eg, an antiviral agent useful for the treatment or prevention of HIV infection or AIDS), "administration" and variations thereof refer to administering the compound and the other agent simultaneously or at different times, respectively. It is understood to include providing to. When the agents of the combination are administered simultaneously, they may be administered together in a single composition or they may be administered separately.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product resulting from combining the specified ingredients. Ingredients suitable for inclusion in pharmaceutical compositions are those that are pharmaceutically acceptable, meaning that the ingredients must be compatible with each other and not deleterious to their recipients.

As used herein, the term “subject” or “patient” refers to an animal, preferably a mammal, and most preferably a human being the subject of treatment, observation or experimentation.

As used herein, the term “effective amount” means to elicit GAG-POL dimerization in HIV-infected cells and selectively kill HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells; means an amount of a compound sufficient to exert a therapeutic effect and/or a prophylactic effect after administration. One embodiment of an “effective amount” of a compound effective in selectively killing HIV-infected GAG-POL expressing cells in an HIV-infected patient, treating HIV infection, or treating AIDS or ARC or delaying the onset or progression thereof. A “therapeutically effective amount” is an amount. Another embodiment of an “effective amount” is a “prophylactically effective amount” which is an amount of a compound effective for the prevention of AIDS or ARC in an HIV-infected patient. It is understood that an effective amount can be both a therapeutically effective amount, eg, for the treatment of HIV infection, and a prophylactically effective amount, eg, for preventing or reducing the risk of developing AIDS or ARC in a subject infected with HIV. As used herein, the term “prevention” refers to reducing the likelihood or severity of AIDS after HIV infection.

In the combination therapy of the present invention, an effective amount may refer to each individual agent or the combination as a whole, wherein the amounts of all agents administered in the combination are effective together, but the component agents of the combination are administered alone. may or may not be present individually in an effective amount with respect to what is considered effective for the component agent.

In the method of the present invention (i.e., selectively killing HIV-infected GAG-POL expressing cells, treating infection by HIV, or treating, preventing or delaying the onset or progression of AIDS or ARC), a compound of the present invention or A salt thereof may be administered by any means that produce contact of the active agent with the site of action of the agent. They may be administered by conventional means available for use with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. The compound may be administered as such, but is typically administered with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice. The compounds of the present invention may be administered, for example, orally (eg, via tablets or capsules), parenterally (including, for example, subcutaneous injection, intravenous, intramuscular or intrasternal injection or infusion techniques), inhalation spray by or rectally, in unit dosage form of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The compound may also be administered via an implantable drug delivery device adapted to provide an effective amount of the compound or pharmaceutical composition of the compound over an extended period of time.

formulation

Solid formulations suitable for oral administration (eg, powders, pills, capsules and tablets) can be prepared according to techniques known in the art and contain solid excipients such as starches, sugars, kaolin, lubricants, binders, disintegrants, and the like. can be used Liquid formulations suitable for oral administration (eg, suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art and employing any conventional medium, such as water, glycols, oils, alcohols, and the like. can Parenteral compositions may be prepared according to techniques known in the art and typically employ sterile water as the carrier and optionally other ingredients, such as solubilizing aids. Injectable solutions can be prepared according to methods known in the art, wherein the carrier includes a solution containing a saline solution, a glucose solution, or a mixture of saline and glucose. Implantable compositions wherein the carrier comprises the active chemical ingredient together with a polymer as suitable excipients or implantable compositions utilizing an implantable device for drug delivery can be prepared according to methods known in the art. Additional descriptions of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and ingredients suitable for use in such compositions are found in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 978 0 85711-062-6] and earlier editions.

Formulations of compounds of formula (I) that cause drug supersaturation and/or rapid dissolution can be used to facilitate oral drug absorption. Formulation approaches that result in drug supersaturation and/or rapid dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for preparing them are known in the art. For example, solid dispersions can be prepared using excipients and methods as described in the review literature (eg, ATM Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). have. Nanoparticulate systems based on both attrition and direct synthesis are also described in review literature, such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

The compound of formula (I) is for example in a dosage range of 1 to 20 mg/kg or 1 to 10 mg/kg or about 5 mg/kg of mammal (eg human) body weight per day, or if appropriate It may be administered as a single dose or in divided doses at different time intervals. The compound of formula (I) may be administered in single or divided doses in a dosage range of 0.001 to 2000 mg per day. Examples of dosage ranges are 0.01 to 1500 mg per day or 0.1 to 1000 mg per day, administered orally or via other routes of administration in single doses or in divided doses.

In the case of oral (eg tablets or capsules) or other routes of administration, dosage units may contain from 100 mg to 1500 mg of active ingredient, including but not limited to 100 mg, for symptomatic adjustment of the dosage to the patient to be treated. , 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400 or 1500 milligrams of active ingredient. Additionally, the compounds may be formulated into oral formulations for immediate or modified release, such as extended or controlled release. Where a compound of formula (I) is administered as a salt, references to the amount (milligrams or grams) of the compound are based on the free form (ie, the non-salt form) of the compound.

Daily administration may be via any suitable route of administration, but is preferably via oral administration, as a single dose or more than one dose staggered within each 24-hour period (in divided daily doses). can be Each dose may be administered using one or multiple dosage units as appropriate.

The specific dose level and frequency of administration for any particular patient may vary and include the activity of the specific compound employed, the metabolic stability and duration of action of that compound, age, weight, general health, sex, diet, mode and time of administration, excretion. It will depend on a variety of factors, including the rate, drug combination, the severity of the particular condition, and the host receiving the therapy. In some cases, depending on the potency of the compound or individual response, it may be necessary to adjust up or down from a given dose. The amount and frequency of administration will be adjusted according to the judgment of the attending clinician taking these factors into account.

An “anti-HIV agent” is any agent that is effective, directly or indirectly, in the inhibition of HIV, in the treatment or prophylaxis of HIV infection, and/or in the treatment, prevention, or delay of the onset or progression of AIDS or ARC. Anti-HIV agents are understood to be effective in treating, preventing or delaying the onset or progression of HIV infection or AIDS and/or a disease or condition resulting from or associated with it. The present disclosure further relates to the use of a compound of formula (I) with one or more compatible anti-HIV agents, ie anti-HIV agents other than HIV protease inhibitors. For example, the compound of formula (I) may be administered in combination with an effective amount of one or more compatible anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infective agents or vaccines useful for treating HIV infection or AIDS. Compatible HIV antiviral agents suitable for use in combination with the compounds of the present disclosure include, but are not limited to, those listed in Table A as follows:

Table A: Antiviral Agents for Treatment of HIV Infection or AIDS

EI = entry inhibitor; FI = fusion inhibitor; InSTI = integrase inhibitor; NRTI = nucleoside or nucleotide reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTTI = nucleoside reverse transcriptase translocation inhibitor. Some of the drugs listed in the table are used in salt form; For example, abacavir sulfate, delavirdine mesylate.

The scope of the combination of a compound of the present invention with a compatible anti-HIV agent is not limited to the HIV antiviral agents listed in Table A, but in principle any pharmaceutical useful for the treatment or prophylaxis of HIV AIDS or ARC, excluding HIV protease inhibitors. It is understood to include any combination with the composition. Compatible HIV antiviral agents and other active agents typically include, for example, the dosages described in the current Physicians' Desk Reference, Thomson PDR, 70th edition (2016), Montvale, NJ: PDR Network, or prior editions thereof. It will be used in these combinations in their usual dosage ranges and regimens as reported in the art. The dosage ranges for the compounds of the present disclosure in these combinations may be the same as set forth above.

The compounds of the present invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of the present invention are useful for the isolation of enzyme mutants, which are excellent screening tools for more potent antiviral compounds. Additionally, the compounds of the present invention are useful for establishing or determining the binding site of other antiviral agents to the reverse transcriptase region in GAG-POL, for example by competitive inhibition.

The following acronyms and abbreviations have the meanings indicated:

Several methods for preparing the compounds of the present invention are described in the Schemes and Examples below. Starting materials and intermediates are either purchased or prepared using known procedures or otherwise prepared as exemplified in the Five Intermediates (A, B, C, AB and BC) section below. Routes frequently applied to the compounds of formula (I) are described in the schemes below.

Scheme 1

Scheme 1 depicts a method for preparing compounds of formula (I). Intermediate AB is prepared by the procedure exemplified in the Intermediate AB section. Mitsunobu reaction or alkylation with an appropriate pyridinone benzyl alcohol or halide (Intermediate C) provides intermediate ABC. Intermediate C typically has a protected (PG′) pyridinone moiety, shown as Z in Scheme 1. The synthesis of C is illustrated in the Intermediate C section. The resulting intermediate ABC can optionally be subjected to further modifications followed by a deprotection step to provide compounds of formula (I).

Scheme 2

Scheme 2 illustrates another method for preparing compounds of formula (I). Intermediate ABC is prepared using the _{SN Ar} reaction between Intermediate A (commercially available or prepared using the procedure in the Intermediate A section) and Intermediate BC (prepared by the procedure illustrated in the Intermediate BC section) . The pyridinone C ring is generally protected with a protecting group (PG'), such as a methyl or PMB group. The resulting intermediate ABC can then optionally be subjected to further modifications followed by a deprotection step to provide compounds of formula (I).

Moisture- or air-sensitive reactions were performed using anhydrous solvents and reagents under nitrogen or argon. Reactions performed using microwave irradiation were typically performed using Emrys Optimizer manufactured by Personal Chemistry or Initiator manufactured by Biotage. Concentration of the solution was carried out on a rotary evaporator under reduced pressure.

The progress of the reaction is usually this. Analytical thin layer chromatography (TLC) or analytical liquid chromatography-mass spectrometry (LC-MS) performed with E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. was determined by Typically, the analytical LC-MS system used consisted of an Agilent 1100 series HPLC with autosampler and a Waters ZQ™ platform with electrospray ionization in cation detection mode. Columns were typically Waters Xterra MS C18, 3.0 x 50 mm, 5 μm or Waters Acquity UPLC® BEH C18 1.0 x 50 mm, 1.7 μm. The flow rate was 1 mL/min and the injection volume was 10 μL. UV detection ranged from 210-400 nm. Mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (acetonitrile plus 0.05% TFA), gradient changed from 100% solvent A for 0.7 min to 100% solvent B over 3.75 min, 1.1 min and then return to 100% solvent A over 0.2 minutes. LC/MS crystallization was carried out using a Waters Classing Acquity System equipped with TUV and MS detectors and a Waters SQD mass spectrometer, Shimadzu 20 UV 254 and 220 nM, or DAD/ELSD and G6110 MSD with a Shimadzu 2010 or 2020 mass spectrometer. performed on an Agilent 1200 HPLC equipped with Ascentis Express C18 (3 x 50 mm) 2.7 μm column at 210 nm using a gradient of 90:10 (A:B) to 5:95 (A:B) over 6 minutes at a flow rate of UV detection; 2) A: mobile phase containing 0.05% trifluoroacetic acid in water and B: 0.05% trifluoroacetic acid in acetonitrile 5 at 90:10 (A:B) over 2 minutes at a flow rate of 0.3 mL/min Acquity BEH C18 (1.0 x 50 mm) 1.7 μm column using a gradient of :95 (A:B), UV detection at 215 nm; 3) A: mobile phase containing 0.1% trifluoroacetic acid and B: acetonitrile in water 95:5 (A:B) to 0:100 (A:B) over 3.6 minutes at a flow rate of 1.4 mL/min and an Agilent YMC J'sphere H-80 (3 x 50 mm) 5 μm column, UV detection at 254 and 220 nm and an Agilent 1100 quadrupole mass spectrometer using a gradient of 0:100 (A:B) for 0.4 min; 4) A: mobile phase containing 0.0375% trifluoroacetic acid in water and B: 0.01875% trifluoroacetic acid in acetonitrile at a flow rate of 0.8 mL/min for 0.4 min at 90:10 (A:B) for 3 min Agilent TC-C18 (2.1 x 50 mm) 5 μm column, 254 and 220 nm using a gradient of 90:10 to 0:100 (A:B) over and 10:90 (A:B) for 0.6 min. UV detection and Agilent 6110 quadrupole mass spectrometer.

Preparative HPLC purification was conventionally performed using either a mass spectrometry directed system or a non-mass guided system. Typically, these are by Waters ZQ™ single quadrupole MS system with electrospray ionization, Waters 2525 gradient pump, Waters 2767 injector/collector, Waters 996 PDA detector, MS conditions: 150-750 amu, positive electrospray, MS Triggered collection, and LC-MS system consisting of a Waters SUNFIRE® C-18 5 micron, 30 mm (id) x 100 mm column was performed on a Waters chromatography workstation. The mobile phase consisted of a mixture of acetonitrile (10-100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL/min, the injection volume was 1800 μL, and the UV detection range was 210-400 nm. The alternative preparative HPLC system used consisted of a Gilson GX-281 injector/collector, a Gilson UV/VIS-155 detector, a Gilson 333 and 334 pump, the following: Phenomenex Synergi C18 (150mm) x 30mm x 4 micrometers), YMC-Actus Pro C18 (150mm x 30mm x 5 micrometers), Xtimate C18 (150mm x 25mm x 5 micrometers), Boston Green ) Gilson Walk with columns selected from ODS (150mm x 30mm x 5 micrometers), XSELECT C18 (150mm x 30mm x 5 micrometers), and Waters XSelect C18 (150mm x 30mm x 5 micrometers) It was a station. Conditions are high pH (0-100% acetonitrile/water eluent with 0.1% v/v 10 mM NH ₄ HCO ₃ or 0.05% NH ₄ OH) or low pH (0-95 with 0.1% v/v TFA) % acetonitrile/water eluent). The injection volume ranged from 1000-8000 μL, and the UV detection range was 210-400 nm. Mobile phase gradients were optimized for individual compounds.

Flash chromatography is typically performed using a Biotage® flash chromatography apparatus (Dyax Corp.), an ISCO CombiFlash® Rf apparatus or an ISCO CombiFlash® Companion XL of the stated size. Performed on silica gel (32-63 μm, 60 Å pore size) in pre-packed cartridges.

SFC chiral resolution was performed on Sepiat Preparative SFC 100, Multigram II (MG II) , THAR80 Preparative SFC, or Waters SFC (80, 200, or 350) using the conditions described in the Experimental section.

Proton or ¹ H NMR is, unless otherwise specified, a Varian 400 ATB PFG 5 mm, Nalorac DBG 400-5 or Varian equipped with a Nalorac IDG 400-5 probe according to standard analytical techniques. Varian Unity-Inova 400 MHz NMR Spectrometer, Varian-400 MHz MR Spectrometer with Auto X ID PFG Probe 5 mm, Varian 400 MHz VNMRS Spectrometer with PFG 4Nuc Probe 5 mm, or PABBO Probe 5 mm was acquired using a Bruker Avance III 500 MHz spectrometer equipped with ¹ H NMR spectra were obtained in _{CDCl 3 solution, unless otherwise indicated.} Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was _{used as internal reference in CD 3} Cl solution and residual CH ₃ OH peak or TMS was used as internal reference _{in CD 3 OD solution.} Coupling constants (J) are reported in hertz (Hz).

It is understood that a chiral center in a compound may exist in the "S" or "R" stereo-configuration, or in mixtures of both. Within the molecule, each bond drawn as a straight line from the chiral center encompasses each (R) and (S) stereoisomer as well as mixtures thereof, unless otherwise indicated. The compounds of Examples 32, 33 and 34 contain chiral centers. Isomer A (the faster eluting isomer) and Isomer B (the more slowly eluting isomer) and eluting isomers) were obtained. The elution time and/or order of the separated isomers may be different when performed under different conditions than those used herein. The absolute stereochemistry (R or S) of the chiral centers in each of the “A” and/or “B” separated stereoisomers in Examples 32, 33 and 34 has not been determined, and “A” and “B” are only performed Refers to the elution sequence resulting from the purification conditions specified. Asterisks (*) may be used in the associated chemical structure drawings of the example compounds to indicate chiral centers.

Intermediate A section

Intermediate A01

3-(difluoromethyl)-5-hydroxybenzonitrile

Step 1: 3-Chloro-5-((4-methoxybenzyl)oxy)benzonitrile

To a solution of 3-chloro-5-hydroxybenzonitrile (30 g, 0.20 mol) in ACN (300 mL) was added PMBCl (34 g, 0.21 mol) and K ₂ CO ₃ (55 g, 0.4 mmol) followed by , the mixture was stirred at 70 °C for 4 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (2% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.33 (d, J=8.0 Hz, 2H), 7.23 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.94 (d, J) = 8.0 Hz, 2H), 5.00 (s, 2H), 3.83 (s, 3H).

Step 2: 3-((4-methoxybenzyl)oxy)-5-vinylbenzonitrile

To a solution of 3-chloro-5-((4-methoxybenzyl)oxy)benzonitrile (50 g, 0.18 mol) in dioxane/H ₂ O (400 mL/80 mL) under _{N 2 atmosphere} Loborate (25 g, 0.18 mol), K ₂ CO ₃ (50 g, 0.36 mol), X-phos (17 g, 36 mmol) and Pd(OAc) ₂ (4.1 g, 18 mmol) were added and the mixture was was stirred at 80 °C for 2 hours. After cooling to room temperature, the resulting mixture was filtered and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (1-2% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.34 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.93 (d, J) = 8.4 Hz, 2H), 6.63 (dd, J= 17.6, 12.0 Hz, 1H), 5.78 (d, J= 17.6 Hz, 1H), 5.38 (d, J= 12.0 Hz, 1H), 5.01 (s, 2H) ), 3.82 (s, 3H).

Step 3: 3-Formyl-5-((4-methoxybenzyl)oxy)benzonitrile

To a stirred solution of compound 3-((4-methoxybenzyl)oxy)-5-vinylbenzonitrile (28 g, 0.1 mol) in dioxane/H _{2 O (180 mL/60 mL) 2,6-lutidine} (22 g, 0.2 mol), OsO ₄ (1.3 g, 5 mmol) and NaIO ₄ (43 g, 0.2 mol) were added and the mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc (3x200 mL). The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2-10% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.95 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.37 (d, J= 8.4 Hz) , 2H), 6.93 (d, J = 8.4 Hz, 2H), 5.14 (s, 2H), 3.73 (s, 3H).

Step 4: 3-(difluoromethyl)-5-((4-methoxybenzyl)oxy)benzonitrile

To a stirred solution of 3-formyl-5-((4-methoxybenzyl)oxy)benzonitrile (22 g, 82 mmol) in DCM (250 mL) _{at 0° C. under N 2} atmosphere (106 g, 0.6 mol) ) was added, and the mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the mixture was quenched with water and extracted with DCM (3 x 200 mL). The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound.

Step 5: 3-(difluoromethyl)-5-hydroxybenzonitrile

A solution of 3-(difluoromethyl)-5-((4-methoxybenzyl)oxy)benzonitrile (23.7 g, 82 mmol) in TFA/TFAA (100 mL/50 mL) at 110° C. for 3 h stirred. When the reaction was complete, the resulting mixture was _{quenched with saturated aqueous NaHCO 3} (100 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.66 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 6.97 (t, J= 56.0 Hz) , 1H).

Intermediate A02

5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile

Step 1: 5-formyl-2-methylbenzonitrile

Into a 20-L four-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 5-bromo-2-methylbenzonitrile (750 g, 38.26 mol) in tetrahydrofuran (6 L), n- BuLi (1.54 L, 38.26 mol) was added dropwise at -78°C, the resulting solution was stirred for 30 minutes, and N,N-dimethylformamide (295 g, 4.04 mol, 1.05 equiv) was added dropwise. The reaction mixture was then stirred in a liquid nitrogen bath at −78° C. for 30 min, then quenched by addition _{of 5 L of saturated aqueous NH 4 Cl.} The resulting solution was extracted with EtOAc (3 x 5 L). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound.

Step 2: 3-Bromo-5-formyl-2-methylbenzamide

To a 3-L four-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-formyl-2-methylbenzonitrile (245 g, 1.69 mol) in sulfuric acid (980 mL), and the reaction mixture was stirred at 60 After stirring at °C, 1-bromopyrrolidine-2,5-dione (300 g, 1.69 mol) was added in 3 batches. The resulting solution was stirred at 60° C. for 30 min. The reaction was then quenched by addition of 5 L of water/ice and stirred for 1 h. The solid was collected by filtration and dried under vacuum to afford the title compound, which was used as such in the next step.

Step 3: 3-Bromo-5-formyl-2-methylbenzonitrile

In a 20-L four-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-bromo-5-formyl-2-methylbenzamide (500 g (crude product from step 2) in dichloromethane (10 L) ), 2.07 mol), and pyridine (524.5 g, 6.63 mol) were added. While the resulting solution was stirred at 0° C., 2,2,2-trifluoroacetate (1305 g, 6.21 mol) was added dropwise. The resulting solution was stirred at room temperature for 30 min, then quenched with water/ice (5 L) and extracted with DCM (3×5 L). The organic layers were combined, _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (20% EtOAc/hexanes) to afford the title compound.

Step 4: 3-Bromo-5-(difluoromethyl)-2-methylbenzonitrile

To a solution of 3-bromo-5-formyl-2-methylbenzonitrile (360 g, 1.61 mol) in dichloromethane (5.4 L) was added DAST (260 g, 1.61 mol, 1.00 equiv) dropwise at room temperature. The resulting solution was stirred at room temperature for 1 h, then quenched with water/ice (3 L). The resulting solution was extracted with DCM (3 x 5 L). The organic layers were combined, _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated under reduced pressure to afford the title compound, which was used as such in the next step.

Step 5: 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile

To a solution of 3-bromo-5-(difluoromethyl)-2-methylbenzonitrile (320 g, 1.30 mol) in 1,4-dioxane (1.6 L) in water (1.6 L) KOH (146 g , 2.60 mol), Pd ₂ (dba) ₃ (67 g, 64.92 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (55 g, 129.53) mmol) was added. The resulting mixture was purged with nitrogen (3x), stirred at 90° C. for 1 h, then partitioned between ice water (4 L) and EtOAc (3x 2 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (33% EtOAc/hexanes) to afford the title compound. MS: 182 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.65 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 6.99 (s, 1H) ), 2.34 (d, J = 1.3 Hz, 3H).

Intermediate A03

2,5-dichloro-3-hydroxybenzonitrile

Step 1: 2-Amino-5-bromo-3-fluorobenzonitrile

To a stirred solution of 2-amino-3-fluorobenzonitrile (5 g, 36.7 mmol) in DMF (50 mL) was added 1-chloropyrrolidine-2,5-dione (5.15 g, 38.6 mmol), The resulting mixture was stirred at 60° C. for 6 hours. The mixture was partitioned between water (200 mL) and EtOAc (2x150 mL). The combined organic layers were washed with brine (3x300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without purification. MS: 171.1 (M+1).

Step 2: 2,5-dichloro-3-fluorobenzonitrile

2-amino-5-chloro-3-fluorobenzonitrile (6.217 g, 36.4 mmol), copper(I) chloride (10.82 g, 109 mmol) and copper(II) chloride (17.15 g) in ACN (60 mL), 128 mmol) was added tert-butyl nitrite (17.34 ml, 146 mmol) at 25° C. for 1 h. The reaction mixture was diluted with water (180 mL) and extracted with EtOAc (3×120 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (10-100% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, chloroform-d): δ ppm 7.51 (dd, J=2.26, 1.65 Hz, 1 H), 7.44 - 7.47 (m, 1 H).

Step 3: 2,5-dichloro-3-((4-methoxybenzyl)oxy)benzonitrile

To a stirred solution of (4-methoxyphenyl)methanol (2.75 g, 19.89 mmol) in DMF (40 mL) at 0° C. was added NaH (1.034 g, 25.9 mmol). The mixture was stirred at 0° C. for 30 min, then 2,5-dichloro-3-fluorobenzonitrile (3.78 g, 19.89 mmol) was added and then stirred at 25° C. for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×150 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the title compound. MS: 308.1 (M+1).

Step 4: 2,5-dichloro-3-hydroxybenzonitrile

To a stirred solution of 2,5-dichloro-3-((4-methoxybenzyl)oxy)benzonitrile (6.13 g, 19.89 mmol) in DCM (60 mL) was added TFA (20 mL) then at 25°C Stirred for 1 hour. Upon completion, the reaction mixture was poured into saturated aqueous NaHCO ₃ (30 mL) and extracted with DCM (3×60 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound, which was used directly without further purification. MS: 187.9 (M-1).

Intermediate A04

3-Bromo-5-chloro-2-fluorophenol

Step 1: 2-(3-Bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

In a solution of 2-bromo-4-chloro-1-fluorobenzene (300 g, 1.43 mol) in hexanes (4.5 L) B ₂ Pin ₂ (363.7 g, 1.43 mol), Ir [(Ome) (1, 5-COD)] ₂ (14.2 g, 21.42 mmol), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (11.5 g, 42.85 mmol) was purged three times with nitrogen was added later. The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by flash chromatography on silica (0-100% EtOAc/petroleum ether) to afford the title compound.

Step 2: 3-Bromo-5-chloro-2-fluorophenol

2-(3-bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (385 g, To a solution of 1.15 mol) was added a solution of sodium hydroxide (138 g, 3.45 mol) in water (3 L), 35% aqueous hydrogen peroxide (390 g, 3.44 mol) at 0°C. The resulting solution was stirred at 0° C. for 2 h, and _{quenched with saturated Na 2} SO ₃ aqueous solution. After the pH of the solution was adjusted to 3-4 with HCl (1 M), the resulting solution was extracted with EtOAc (3×3 L). The combined organic layers were washed with brine and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica (0-90% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.31 (br. s., 1H), 7.47 (dd, J = 2.4, 4.4 Hz, 1H), 7.30 (dd, J = 2.4, 7.6 Hz, 1H).

Intermediate A05

5-Chloro-2-fluoro-3-hydroxybenzonitrile

To a solution of 3-bromo-5-chloro-2-fluorophenol (86 g, 343 mmol) in NMP (860 mL) was added CuCN (154 g, 1.72 mol) in one portion. The resulting reaction mixture was stirred at 180° C. for 2 h, then partitioned between ice water (1 L) and EtOAc (3×800 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2-33% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.33 (br. s., 1H), 7.49 (dd, J = 2.5, 4.5 Hz, 1H), 7.30 (dd, J = 2.5, 7.6 Hz, 1H) ).

Intermediate A06

5-Chloro-3-hydroxy-2-methylbenzonitrile

Step 1: 2,3-difluorobenzaldehyde

To a solution of 1,2-difluorobenzene (1668 g, 14.62 mol) in THF (16.7 L) cooled at -78°C was stirred with a THF solution of n-BuLi (6.44 L, 16.08 mol) over 60 min. was added dropwise. DMF (5340 g, 73.06 mol) was then added dropwise to this mixture with stirring at -78°C over 60 minutes. The resulting solution was stirred at -78°C for 1 hour. The reaction was then quenched with saturated aqueous NH ₄ Cl (10 L) and then extracted with EtOAc (3×10 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2% EtOAc/petroleum ether) to afford the title compound.

Step 2: (E)-N-[(2,3-difluorophenyl)methylidene]hydroxylamine

A mixture of 2,3-difluorobenzaldehyde (2410 g, 16.96 mol) in a 70% solution _{of NH 2} OH (672 g, 20.35 mol) in DMF (10 L) was stirred at 20° C. for 3 h, then water Partition between (6 L) and EtOAc (3 x 8 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2% EtOAc/petroleum ether) to afford the title compound.

Step 3: 2,3-difluorobenzonitrile

A solution of (E)-N-[(2,3-difluorophenyl)methylidene]hydroxylamine (2025 g, 12.89 mol) in DMF (11 L) was treated with POCl ₃ (5688 g, 37.10 mol) did The resulting solution was stirred at 25° C. for 3 h and then partitioned between water (6 L) and EtOAc (3×6 L). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (2% EtOAc/petroleum ether) to afford the title compound.

Step 4: 2-Amino-3-fluorobenzonitrile

In a sealed reactor, a solution of 2,3-difluorobenzonitrile (1273 g, 9.15 mol) in EtOH (13 L) was bubbled in NH ₃ (gas). The resulting solution was stirred at 140° C. for 8 h, cooled to room temperature, and then concentrated under reduced pressure. The residue was partitioned between water (5 L) and MTBE (3 x 8 L). The combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound.

Step 5: 2-Amino-5-chloro-3-fluorobenzonitrile

A solution of 2-amino-3-fluorobenzonitrile (934 g, 6.86 mol) in DMF (14 L) was treated with NCS (1008 g, 7.55 mol). The resulting solution was stirred at 45° C. for 2 h and then partitioned between ice water (20 L) and EtOAc (3×12 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (3% EtOAc/petroleum ether) to afford the title compound.

Step 6: 2-Bromo-5-chloro-3-fluorobenzonitrile

To a mixture of t-BuONO (815 g, 7.88 mol) and CuBr ₂ (1365 g, 6.13 mol) in ACN (8 L) 2-amino-5-chloro-3-fluorobenzonitrile in ACN (7 L) ( 747 g, 4.38 mol) was added dropwise with stirring over 90 min. The resulting mixture was stirred at room temperature for 10 h, diluted with water (15 L) and then extracted with EtOAc (3 x 10 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (3% EtOAc/petroleum ether) to afford the title compound.

Step 7: 5-Chloro-3-fluoro-2-methylbenzonitrile

2-bromo-5-chloro-3-fluorobenzonitrile (768 g, 3.28 mol), 1,4-methylboronic acid ( A mixture of 297 g, 4.96 mol), potassium carbonate (913 g, 6.61 mol) and PdCl ₂ (dppf) (213 g, 0.33 mol) was stirred at 100° C. for 60 min, then diluted with water (4 L), Extracted with EtOAc (3 x 6 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (3% EtOAc/petroleum ether) to afford the title compound.

Step 8: 5-Chloro-3-[(4-methoxyphenyl)methoxy]-2-methylbenzonitrile

Under nitrogen atmosphere, to a solution of 4-methoxybenzyl alcohol (410 g, 2.97 mol) in DMF (3200 mL) was added sodium hydride (128 g, 5.33 mol) followed by 5-chloro- in DMF (800 mL) A solution of 3-fluoro-2-methylbenzonitrile (418 g, 2.46 mol) was added dropwise. The resulting solution was stirred at 25° C. for 12 h, then diluted with ice water (2 L) and extracted with EtOAc (3×3 L). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting solid was washed with petroleum ether and collected on top of a filter to afford the title compound.

Step 9: 5-Chloro-3-hydroxy-2-methylbenzonitrile

A solution of 5-chloro-3-[(4-methoxyphenyl)methoxy]-2-methylbenzonitrile (518 g, 1.80 mol) in DCM (1500 mL) was treated with TFA (500 mL). The resulting solution was stirred at 25° C. for 1 hour. The solid was collected on top of a filter to give the title compound. MS: 166 (M-1). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (s, 1H), 7.32-7.33 (d, 1H), 7.07-7.08 (d, 1H), 2.24 (s, 3H).

Intermediate A07

5-Fluoro-3-hydroxy-2-methylbenzonitrile

Step 1: 3-Bromo-5-fluoro-2-methylaniline

To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (23 g, 98 mmol) in ethanol (390 mL) ammonia hydrochloride (26.3 g, 491 mmol) and water (38.3 ml, 2126 mmol), followed by iron (27.4 g, 491 mmol). The resulting mixture was stirred at 90° C. for 6 hours. After completion of the reaction monitored by TLC, the reaction mixture was filtered through a sintered funnel. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica (5% EtOAc/petroleum ether) to give the title compound. MS: 204.2 and 206.2 (M+1).

Step 2: 3-Bromo-5-fluoro-2-methylphenol

To a solution of sulfuric acid (145 mL, 2729 mmol) in water (21.73 mL, 1206 mmol) was added 3-bromo-5-fluoro-2-methylphenol (7 g, 31.1 mmol). The resulting mixture was cooled to 0° C. using an ice bath. Then a solution of sodium nitrate (6.66 g, 78 mmol) in water was added dropwise. After stirring at this temperature for 30 min, the reaction mixture was heated at 100 °C for 30 min, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (4-10% EtOAc/petroleum ether) to give the title compound. MS: 203.2 and 205.2 (M-1).

Step 3: 5-Fluoro-3-hydroxy-2-methylbenzonitrile

To a stirred solution of 3-bromo-5-fluoro-2-methylphenol (7 g, 34.1 mmol) in DMA (140 mL) was added zinc dust (4.46 g, 68.3 mmol) and dppf (3.79 g, 6.83 mmol) added. The resulting mixture was degassed with nitrogen for 10 min, then Pd ₂ (dba) ₃ (1.563 g, 1.707 mmol) and zinc cyanide (8.02 g, 68.3 mmol) were added. The reaction vessel was sealed. The resulting mixture was heated to 140° C. for 6 h, then diluted with water (200 mL) and filtered through a layer of CELITE®. The filter cake was washed with EtOAc (400 mL). The layers of the filtrate were separated. The aqueous layer was further extracted with EtOAc (2x200 mL). The combined organic layers were washed with brine (2x200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (5-15% EtOAc/petroleum ether) to give the title compound. MS: 150.2 (M-1).

The following intermediates in Table 1 were purchased from commercial sources.

Table 1

Intermediate B section

Intermediate B01

5-Fluoro-6-(1,1,2,2-tetrafluoroethyl)-3,4-dihydropyrimidin-4-one

Step 1: 2,2,3,3-tetrafluoropropanoic acid

To a solution of potassium heptaoxodichromium (1782 g, 6.06 mol) in sulfuric acid (2097 g, 21.38 mol) and water (2400 mL) 2,2,3,3-tetrafluoropropan-1-ol (800 g, 6.06 mol) was added dropwise with stirring at 100°C. The resulting solution was stirred at 100° C. under reflux for 5 hours, then extracted with MTBE (4×2 L). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, which was used as such in the next step.

Step 2: 2,2,3,3-tetrafluoro-N-methoxy-N-methylpropanamide

To a solution of 2,2,3,3-tetrafluoropropanoic acid (crude product from previous step, 45% purity, 1007 g, 3.15 mol) in THF (4600 mL) sulfuroyl dichloride (787.2 g, 6.62 mol) ) was added dropwise at 0° C., followed by DMF (753.4 g, 10.31 mol) dropwise. After stirring at room temperature for 45 min, the reaction mixture was cooled to 0° C. and then treated dropwise with methoxy(methyl)amine hydrochloride (1222.5 g, 12.53 mol) and TEA (1913 g, 18.91 mol). The resulting mixture was stirred at room temperature for 5 h, then quenched with ice water (2 L) and extracted with MTBE (3 L). The organic layer was _{washed with saturated aqueous NaHCO 3} , brine, dried over anhydrous sodium sulfate, filtered and distilled to afford the title compound.

Step 3: Ethyl 2,4,4,5,5-pentafluoro-3-oxopentanoate

To a solution of 2,2,3,3-tetrafluoro-N-methoxy-N-methylpropanamide (470 g, 2.49 mol) in THF (4700 mL) at -78 ° C. g, 2.98 mol), a 1M solution of LiHMDS in THF (3729 mL, 3.73 mol). The resulting mixture was stirred at -78 °C for 2 h, _{then quenched with saturated aqueous NH 4} Cl (1 L). After the pH value of the solution was adjusted to 3 with HCl (1M), the reaction mixture was extracted with MTBE (3x2L). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step.

Step 4: 5-Fluoro-6-(1,1,2,2-tetrafluoroethyl)-3,4-dihydropyrimidin-4-one

In a solution of ethyl 2,4,4,5,5-pentafluoro-3-oxopentanoate (533 g, 2.28 mol) in methanol (5330 mL) formamidine acetate (1185.1 g, 11.38 mol) and sodium Methoxide (492 g, 9.11 mol) was added. The resulting mixture was stirred at room temperature for 2 h, then quenched with ice water (1.5 L). After the pH value of the solution was adjusted to 3 with HCl (2M), the resulting mixture was extracted with MTBE (3x 1 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization from MTBE/PE (1:5) to afford the title compound. MS: 212.9 (M-1). ¹ H NMR: (300 MHz, CD ₃ OD): δ 8.10 (1H, s), 6.67-6.38 (1H, m).

Intermediates in Table 2 below were prepared using the known fluorinated alkyl alcohols or their corresponding acids or methyl esters using the procedure outlined for the synthesis of Intermediate B01 according to Scheme C.

Table 2

Intermediate B05

4-Chloro-5-fluoro-6-methoxypyrimidine

To a solution of 4,6-dichloro-5-fluoropyrimidine (8.0 g, 47.9 mmol) in MeOH (80 mL) at 0° C. was added sodium methoxide (3.05 g, 56.5 mmol). The resulting reaction mixture was stirred at 20° C. for 2 h, then quenched with water (20 ml) and then extracted with EA (3×20 mL). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound. MS: 163.1 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.45(s, 1H), 4.03(s, 1H).

Intermediate B06

4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine

Pd in a solution of 4-chloro-5-fluoro-6-methoxypyrimidine (5.2 g, 28.8 mmol), tributyl(1-ethoxyvinyl)stannane (12.48 g, 34.5 mmol) in DMF (50 ml) (Ph ₃ P) ₄ (0.5 g, 0.433 mmol) was added. The resulting reaction mixture was stirred at 100° C. under _{N 2 atmosphere for 4 hours.} Upon completion, the reaction was diluted with water (30 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were treated with saturated aqueous KF (80 mL), stirred at room temperature for 0.5 h, then passed through a CELITE® bed filter. The filtrate was washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10-90% EtOAc/PE) to afford the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.49 (s, 1H), 5.08 (d, J = 2.8 Hz, 1H), 4.64 (d, J = 3.2 Hz, 1H), 4.06 (s, 3H), 3.93 (m, 2H), 1.42 (m, 3H).

Intermediate B07

6-Acetyl-5-fluoropyrimidin-4(3H)-one

To a solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine (4.5 g, 20.43 mmol) in THF (30 ml) was added 6M aqueous HCl (20 mL, 120 mmol) at 0° C. was added dropwise. The resulting reaction solution was stirred at 20°C for 18 hours, and then concentrated under reduced pressure while maintaining the bath temperature at 40°C to obtain the title compound. ¹ H NMR (400 MHz, d ₆ -DMSO): δ 8.15(s, 1H), 2.50(s, 3H).

Intermediate B08

1-(5-Fluoro-6-methoxypyrimidin-4-yl)ethanone

To a stirred solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine, B06 (12 g, 60.5 mmol) in 1,4-dioxane in ACN (100 mL) at 0 °C A 4M solution of hydrochloric acid (30 mL, 120 mmol) was added dropwise. The resulting solution was stirred at room temperature for 1 h, then carefully quenched with ice cold water (200 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-20% EtOAc/petroleum ether) to give the title compound. MS: 171.4 (M+1).

Intermediate B09

5-Fluoro-6-(1,1,2-trifluoroethyl)pyrimidin-4(3H)-one

Step 1: 2-Fluoro-1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone

A solution of 4-(1-ethoxyvinyl)-5-fluoro-6-methoxypyrimidine, B06 (0.2 g, 0.86 mmol) in ACN (3 mL) was mixed with ACN (2 mL) and water (1 mL) To a suspension of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.456 g, 1.29 mmol) in It was added dropwise over 4 hours. The reaction mixture was then quenched with saturated aqueous NaHCO ₃ (10 mL) and allowed to stir for 10 min. After completion, the mixture was extracted with EA (3x10 mL). The combined organic layers were washed with brine, _{dried over MgSO 4} , filtered and concentrated under reduced pressure to afford the title compound. MS: 189.1 (M+1).

Step 2: 5-Fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrimidine

To a solution of 2-fluoro-1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone (0.15 g, 0.60 mmol) in DCM (2 mL) was diethylaminosulfur trifluoride ( 0.578 g, 3.59 mmol) was added. The resulting reaction mixture was stirred at 20° C. for 4 h, then diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/PE) to afford the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 4.99 (t, J=12.0 Hz, 1H), 4.88 (t, J=12.0 Hz, 1H), 4.12 (s, 3H).

Step 3: 5-Fluoro-6-(1,1,2-trifluoroethyl)pyrimidin-4(3H)-one

A mixture of 5-fluoro-4-methoxy-6-(1,1,2-trifluoroethyl)pyrimidine (0.05 g, 0.238 mmol) and KI (0.119 g, 0.714 mmol) in ACN (15 mL) was added chlorotrimethylsilane (0.078 g, 0.714 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 4 h, then diluted with EtOAc, washed with aqueous Na ₂ S ₂ O ₃ and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to the title compound was obtained. MS: 197.1 (M+1).

Intermediate B10

5-Fluoro-6-methoxypyrimidine-4-carboxylate

A solution of 4-chloro-5-fluoro-6-methoxypyrimidine, B05 (410 g, 2.52 mol), triethylamine (1.247) in MeOH (8.2 L) in a 20-L sealed tube purged with _{N 2} kg, 12.32 mol), PdCl ₂ (dppf) (201 g, 246.32 mmol). Then in a bombe vessel set up for carbonylation with 2 bar of CO and heated at 50° C. for 16 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure to remove MeOH, then diluted with EtOAc (4 L). The solid was filtered off. The filtrate was again concentrated under reduced pressure. The residue was purified by column chromatography on silica (10% EtOAc/hexanes) and then recrystallized (propan- ₂ -ol:H 2 O=2:7) to give the title compound. MS: 187 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.587 (s, 1H), 4.109-4.075 (s, 3H), 4.003-3.935 (s, 3H).

Intermediate B11

Methyl 5-fluoro-6-hydroxypyrimidine-4-carboxylate

Trimethylsilyl chloride (25.7 ml, 201 mmol) was dissolved in ACN (300 mL) with methyl 5-fluoro-6-methoxypyrimidine-4-carboxylate, B09 (25 g, 134 mmol) and potassium iodide ( 33.4 g, 201 mmol) was slowly added to the stirred slurry at 25°C. The resulting mixture was stirred at 25° C. for 2 h. LCMS showed the reaction was complete. The reaction was quenched with methanol (100 mL) and concentrated to give the title compound, which was used in the next step without further purification. MS: 173.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.12 (s, 1H), 2.59 (s, 3H).

Intermediate B12

5-Bromo-6-(trifluoromethyl)pyrimidin-4(3H)-one

This intermediate was prepared via bromination of 6-(trifluoromethyl)pyrimidin-4(3H)-one using the procedure reported in US20140100231(A1).

Intermediate B13

6-Acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one

To a solution of 6-acetyl-5-fluoropyrimidin-4(3H)-one, B07 (1.0 g, 5.44 mmol) in DMF (10 mL) was added K ₂ CO ₃ (2.257 g, 16.33 mmol). The resulting reaction mixture was stirred at 20° C. for 10 minutes, then 1-(chloromethyl)-4-methoxybenzene (1.023 g, 6.53 mmol) was added. The reaction mixture was stirred at 20° C. for an additional 6 h, then diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (50% EtOAc/PE) to afford the title compound. MS: 277.1 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.29 (m, 2H), 6.89 (d, J =8.8, 2H), 5.09 (s, 2H), 3.81 (s, 2H) , 2.58 (d, J =8.8, 3H).

Intermediates in Table 3 below were prepared using the corresponding Intermediate B under conditions analogous to the above synthetic procedures outlined for the synthesis of Intermediate B13.

Table 3

Intermediate B19

5-Bromo-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

This intermediate was prepared using the procedure reported in US20140100231 (A1).

Intermediate B20

5-Bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one

This intermediate was prepared using the procedure reported in US20140100231 (A1).

Intermediate C section

Intermediate C01

(6-chloro-2-methoxypyridin-3-yl)methanol

Step 1: 6-Chloro-2-methoxynicotinaldehyde

To a stirred mixture of t-BuLi (23.94 mL, 38.3 mmol) in THF (100 mL) at -78°C was added 2-chloro-6-methoxypyridine (5 g, 34.8 mmol). The resulting mixture was stirred at -78 °C for 1 h, then DMF (3.51 mL, 45.3 mmol) was added, and the reaction mixture was stirred at -78 °C for 1.5 h, then at -78 °C acetic acid (3.99 mL, 69.7 mmol). The mixture was then warmed to 20° C. over 30 min. The mixture was neutralized with saturated aqueous NaHCO ₃ solution (200 mL) and extracted with EtOAc (3×50 mL). The combined organic fractions were washed with brine (3x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (1-2% EtOAc/isohexane) to give the title compound.

Step 2: (6-Chloro-2-methoxypyridin-3-yl)methanol

To a suspension of 6-chloro-2-methoxynicotinaldehyde (1 g, 5.83 mmol) in MeOH (12 mL) at 0° C. was added sodium borohydride (0.140 g, 3.70 mmol) portionwise over a period of 20 min. The resulting mixture was allowed to stir at 0° C. for 40 min, then quenched with water and extracted with DCM (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford the title compound, which was used as such in the next step. MS: 174.1 (M+1).

Intermediate C02

(6-bromo-2-methoxypyridin-3-yl)methanol

Step 1: 6-Bromo-2-methoxynicotinic acid

To a stirred solution of 2,2,6,6-tetramethylpiperidine (3.76 g, 26.6 mmol) in THF (50 mL) at -78 °C a 2.5 M solution of n-BuLi in THF (10.64 mL, 26.6 mmol) was added dropwise. The resulting mixture was stirred at the same temperature for 60 min, then a solution of 2-bromo-6-methoxypyridine (5 g, 26.6 mmol) in THF was added dropwise. The reaction mixture was stirred at the same temperature for 60 min, treated with crushed dry ice powder, added, stirred at -78°C for 3 h, then allowed to warm slowly to room temperature and diluted with water. The pH of the mixture was then adjusted to 3-4 with concentrated HCl. The mixture was extracted with EtOAc (2x250 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (50% EtOAc/petroleum ether) to give the title compound. MS: 230.2 and 232.0 (M-1).

Step 2: (6-bromo-2-methoxypyridin-3-yl)methanol

To a stirred solution of 6-bromo-2-methoxynicotinic acid (2.3 g, 9.91 mmol) in THF (20 mL) was added dropwise a 1M solution of LAH in THF (19.82 mL, 19.82 mmol) at -20°C. The resulting mixture was stirred at room temperature for 60 min, then quenched with water (0.5 mL), 10% aqueous NaOH solution and water. The resulting mixture was stirred for 30 minutes and filtered through a bed of Celite®. The filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified first by column chromatography on silica (30% EtOAc/petroleum ether) followed by reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford the title compound. MS: 217.4 and 219.4 (M+1).

Intermediate C03

(2-Methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-3-yl)methanol

1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3, in 1,4-dioxane (2 mL) and water (1.0 mL) 2-dioxaborolan-2-yl)-1h-pyrazole (113 mg, 0.406 mmol), (6-chloro-2-methoxypyridin-3-yl)methanol, C01 (47 mg, 0.271 mmol), and potassium phosphate tribasic (172 mg, 0.812 mmol) was purged with nitrogen for 5 min, then [1,1'-bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (19.81 mg, 0.027 mmol) (19.81 mg, 0.027 mmol) ) was added. The resulting mixture was stirred at 80° C. for 15 hours and then passed through a filter. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 290.1 (M+1).

The following intermediates in Table 4 were prepared using a similar procedure outlined for Synthetic Intermediate C03 using the corresponding commercially available boronic acid or boronate.

Table 4

Intermediate C08

1-(5-(chloromethyl)-6-methoxypyridin-2-yl)ethanone

Step 1: (6-(1-ethoxyvinyl)-2-methoxypyridin-3-yl)methanol and 1-(5-(hydroxymethyl)-6-methoxypyridin-2-yl)ethanone

(6-chloro-2-methoxypyridin-3-yl)methanol, C01 (1 g, 5.76 mmol), and tributyl (1-ethoxyvinyl)stannane (4.16 g, 11.52 mmol) in DMF (5 mL) ) was added Pd(Ph ₃ P) ₄ (0.200 g, 0.173 mmol). The resulting mixture _{was stirred under N 2} atmosphere at 100° C. for 4 h, then cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were treated with saturated aqueous KF solution (45 mL) and 4M aqueous HCl solution, stirred at 20° C. for 0.5 h, then washed with brine (2×75 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and It was concentrated under reduced pressure. The residue was purified by column chromatography on silica (1-25% EtOAc/petroleum ether) to afford the title compound. MS: 182.1 (M+1).

Intermediate C09

(4-chloro-6-methoxy-2-methylpyrimidin-5-yl)methanol

Step 1: Methyl 2-chloro-4,6-dimethylnicotinate

To 2-chloro-4,6-dimethylnicotinic acid (2 g, 10.78 mmol) was slowly added sulfurous acid dichloride (20 mL, 275 mmol). The resulting mixture was stirred at 80° C. for 2 h and then concentrated under reduced pressure. The residue was treated with MeOH (20 mL) at 0° C., then the reaction mixture was stirred at 20° C. for 16 h and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 200.1 (M+).

Step 2: Methyl 2-methoxy-4,6-dimethylnicotinate

To a solution of methyl 2-chloro-4,6-dimethylnicotinate (2.206 g, 11.05 mmol) in MeOH (20 mL) at 0° C. was added sodium methanolate (3.58 g, 66.3 mmol). The resulting mixture was stirred at 60° C. for 24 h, then quenched with water (20 mL) and then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 196.1 (M+1).

Step 3: 2-Methoxy-4,6-dimethylpyridin-3-yl)methanol

To a solution of methyl 2-methoxy-4,6-dimethylnicotinate (500 mg, 2.56 mmol) in THF (5 ml) at 0° C. was added LAH (97 mg, 2.56 mmol). The resulting mixture was stirred at 20° C. for 1 h, then quenched with saturated ammonium chloride solution and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC plate (25% EtOAc/petroleum ether) to afford the title compound. MS: 168.3 (M+1).

Intermediate C10

(5-Fluoro-2-methoxypyridin-3-yl)methyl methanesulfonate

Step 1: 5-Fluoro-2-methoxynicotinic acid

A mixture of sodium methoxide (5.70 g, 106 mmol) and methyl 2-chloro-5-fluoronicotinate (2 g, 10.55 mmol) in THF (15 mL) was stirred at 100° C. for 48 h, then H ₂ O (30 mL), acidified to pH=3-4 with HCl (1 M), then extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step without further purification. MS: 170 (M-1).

Step 2: (5-Fluoro-2-methoxypyridin-3-yl)methanol

To a solution of 5-fluoro-2-methoxynicotinic acid (800 mg, 4.67 mmol) in THF (10 ml) was added LAH (266 mg, 7.01 mmol). The resulting mixture was stirred at 25° C. for 5 min, then it was quenched with water (0.27 mL), and aqueous NaOH solution (0.27 mL). The mixture was filtered. The filtrate was extracted with EtOAc (3x30 mL), _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without purification. MS: 158 (M+1).

Intermediate C11

(2-methoxypyridin-3-yl)methanol

Step 1: Methyl 2-methoxynicotinate

To a stirred solution of 2-methoxynicotinic acid (1 g, 6.53 mmol) in methanol (10 mL) at 0° C. was added H ₂ SO ₄ (0.696 mL, 13.06 mmol). The resulting mixture was stirred at 65° C. for 6 hours and then concentrated under reduced pressure to afford the title compound. MS: 168.4 (M+1).

Step 2: (2-methoxypyridin-3-yl)methanol

To a stirred solution of methyl 2-methoxynicotinate (500 mg, 2.99 mmol) in THF (6 mL) was slowly added a 1M solution of LAH in THF (5.98 mL, 5.98 mmol) at 0 °C. The resulting mixture was allowed to warm to room temperature, stirred for 6 h, then cooled and _{quenched with saturated aqueous Na 2} SO ₄ solution and EtOAc. The reaction mixture was filtered through a bed of Celite®. The filter cake was washed with excess EtOAc. The filtrate was separated. The organic layer was concentrated under reduced pressure to give the title compound. MS: 140.4 (M+1).

Intermediate C12

(2-chloro-4,6-dimethylpyridin-3-yl)methanol

A solution of 2-chloro-4,6-dimethylnicotinic acid (300 mg, 1.616 mmol) was dissolved in THF (3 mL) and a 1M solution of LAH in THF (1.616 mL, 1.616 mmol) was added at 0° C. for a period of 10 min. was added dropwise. The resulting mixture was allowed to stir at 0° C. for 2 h, then allowed to warm to ambient temperature and stirred over the weekend. LCMS showed complete conversion to the desired product. The reaction mixture was diluted very slowly with water (~1 mL) and the organic solvent was evaporated under reduced pressure, then partitioned between EtOAc (10 mL) and water (5 mL). The aqueous layer was further extracted with EtOAc (2x10 mL). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 172.0 (M+1).

Intermediate C13

6-Chloro-3-(chloromethyl)-2-methoxypyridine

A solution of (6-chloro-2-methoxypyridin-3-yl)methanol, C01 (500 mg, 2.88 mmol) in DCM (14 mL) was mixed with triethylamine (0.803 mL, 5.76 mmol) followed by mesyl-Cl ( 0.247 mL, 3.17 mmol) dropwise. The resulting reaction mixture was allowed to stir at 23° C. overnight and then partitioned between _{DCM and saturated aqueous NaHCO 3 solution.} The organic layer was separated, _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-20% EtOAc/hexanes) to give the title compound. MS: 192.0 (M+1). ¹ H NMR (600 MHz, chloroform-d) δ 7.58 (d, J=7.7 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 4.53 (s, 2H), 3.99 (s, 3H).

The following intermediates in Table 5 were prepared using the appropriate (6-methoxypyrimidin-5-yl)methanol Intermediate C as starting material described in Table C12 using a similar procedure outlined for Synthetic Intermediate C12.

Table 5

Intermediate C24

5-Bromo-3-(chloromethyl)-2-methoxypyridine

Intermediate C24 was synthesized using a procedure analogous to Intermediate C12 using commercially available (5-bromo-2-methoxypyridin-3-yl)methanol in place of Intermediate C01.

Intermediate AB section

Intermediate AB01

5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl )oxy)benzonitrile

Step 1: 5-(difluoromethyl)-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6 -dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-fluoro-3-(4-methoxybenzyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one, B16 (7) in NMP (46.5 mL) g, 20.94 mmol) was added 5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (4.22 g, 23.04 mmol) and K ₂ CO ₃ (8.68 g, 62.8 mmol) did The resulting mixture was stirred at 80° C. overnight. LCMS showed complete conversion. The reaction mixture was cooled to room temperature and then diluted with water. The precipitate was collected on top of the filter, washed with water (3x) and then air-dried to afford the title compound. MS: 498.1 (M+1).

Step 2: 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine- 5-yl)oxy)benzonitrile

5-(difluoromethyl)-3-((1-(4-methoxybenzyl)-6-oxo-4-(1,1,2,2-) in TFA (66.3 mL) and TFAA (33.1 mL) A solution of tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (9.89 g, 19.88 mmol) was stirred at 50° C. overnight. LCMS showed complete conversion. The reaction mixture was concentrated under reduced pressure. The residue was triturated with hexanes and the solid was collected on top of a filter, washed with hexanes and then air dried to give the title compound, which was used directly in the next step with further purification. MS: 378.3 (M+1).

The following intermediates in Table 6 were prepared in a similar manner to intermediate AB01 described above: SN _Ar reaction using the corresponding intermediates A and B, followed by deprotection using TFA/TFAA to remove the PMB group.

Table 6

Intermediate AB12

5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 6-Acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one

To a solution of 6-acetyl-5-fluoro-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B13 (2 g, 7.24 mmol) in DMF (10 mL) 3-bromo- 5-Chloro-2-fluorophenol, A04 (1.959 g, 8.69 mmol) and K ₂ CO ₃ (2.01 g, 14.48 mmol) were added. The resulting mixture was stirred at 60° C. for 4 h, then _{poured into H 2} O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (2-3.3% MeOH/DCM) to give the title compound.

Step 2: 5-(3-Bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidine-4(3H)- On

6-Acetyl-5-(3-bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (300 in THF (2 mL) _{mg, 0.623 mmol) was added a 0.1 M solution of Zn(BH 4} ) ₂ in THF (0.934 mL, 0.093 mmol) at -30° C. and the mixture was stirred for 10 min. To the reaction mixture was added water (1 drop) and then concentrated under reduced pressure to give the title compound.

Step 3: 5-(3-Bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidine-4(3H)- On

5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-hydroxyethyl)-3-(4-methoxybenzyl)pyrimidine-4 ( To a solution of 3H)-one (680 mg, 1.406 mmol) at 0° C. was added DAST (0.427 mL, 3.23 mmol). The resulting reaction mixture was stirred at 0° C. for 1 h, then diluted with water (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound.

Step 4: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-5 -yl)oxy)benzonitrile

5-(3-bromo-5-chloro-2-fluorophenoxy)-6-(1-fluoroethyl)-3-(4-methoxybenzyl)pyrimidine-4 ( To a stirred solution of 3H)-one (340 mg, 0.700 mmol) was added _{cyanocopper (217 mg, 2.423 mmol) under N 2 .} The resulting mixture was stirred at 170° C. for 12 h, _{then diluted with H 2} O (30 mL) and EtOAc (30 mL). The mixture was filtered through a Celite® funnel. The filtrate was extracted with EA (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was triturated with MeOH (20 mL) to give the title compound.

Step 5: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyri in TFA (1.5 mL) To a solution of midin-5-yl)oxy)benzonitrile (0.217 g, 0.503 mmol) was added TFAA (0.75 mL). The resulting mixture was stirred at 100° C. for 6 h, then diluted with DCM (10 mL) and concentrated under reduced pressure to afford the title compound.

Intermediate AB13

5-Chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile

Step 1: Methyl 5-fluoro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate

Potassium carbonate (16.11 g, 117 mmol) was dissolved in methyl 5-fluoro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-car in dimethylacetamide (350 mL). To a mixture of carboxylate, B15 (21.29 g, 72.9 mmol) and 5-chloro-2-fluoro-3-hydroxybenzonitrile, A05 (10 g, 58.3 mmol) at 25°C. The resulting mixture was stirred at 90° C. overnight. LCMS showed the desired product and a clear reaction. Water (500 mL) was added and a precipitate formed. The mixture was filtered and the solid was washed with water (100 mL) and hexanes (200 mL) and dried under high vacuum overnight to afford the title compound. MS: 444 (M+1).

Step 2: 5-(5-Chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxyl Mountain

Potassium trimethylsilanolate (9.97 g, 78 mmol) was dissolved in methyl 5-(5-chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)- in THF (345 mL)- To a stirred mixture of 6-oxo-1,6-dihydropyrimidine-4-carboxylate (23 g, 51.8 mmol). The resulting mixture was stirred at 25° C. for 1 hour. LCMS showed only the desired product. HCl (1N aq., 300 mL) was added slowly and a white solid formed. The mixture was concentrated under reduced pressure to remove THF. The mixture was filtered and the white solid was washed with water and dried under vacuum to afford the title compound. MS: 430.0 (M+1).

Step 3: 5-(5-Chloro-3-cyano-2-fluorophenoxy)-N-methoxy-1-(4-methoxybenzyl)-N-methyl-6-oxo-1,6- Dihydropyrimidine-4-carboxamide

5-(5-Chloro-3-cyano-2-fluorophenoxy)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4 in DMF (200 mL) -Carboxylic acid (20 g, 46.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.99 g, 51.2 mmol) in a flask at 25 °C with triethylamine (25.9 ml, 186 mmol) followed by EDC ( 9.81 g, 51.2 mmol) and HOBt (7.84 g, 51.2 mmol) were added. The resulting mixture was stirred at 25° C. overnight. LCMS showed the reaction was complete. Water (300 mL) was added and the resulting precipitate was filtered, washed with water and dried under vacuum to afford the title compound. MS: 473.1 (M+1).

Step 4: 3-((4-Acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzo nitrile

Methylmagnesium bromide (3M in THF, 40 mL, 120 mmol) was dissolved in 5-(5-chloro-3-cyano-2-fluorophenoxy)-N-methoxy-1-(4) in THF (350 mL). -Methoxybenzyl)-N-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (16.5 g, 34.9 mmol) was added dropwise to a cooled (-78°C) mixture. The resulting mixture was stirred at -78 °C for 3 h. LCMS showed the desired product, but was still the starting material. The reaction mixture was then warmed to 0° C. and stirred for 30 min. LCMS showed the reaction was complete. The reaction was quenched with saturated aqueous NH ₄ Cl solution (500 mL) and diluted with EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x200 mL). The combined organic layers were washed with brine (500 mL), _{dried over anhydrous MgSO 4} , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 428.0 (M+1).

Step 5: 5-Chloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl )oxy)-2-fluorobenzonitrile

Deoxofluor® (15.08 ml, 82 mmol) was mixed with 3-((4-acetyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl) Oxy)-5-chloro-2-fluorobenzonitrile (7 g, 16.36 mmol) and dichloroethane (9.35 ml) were added to a vial at 25°C. The resulting vial was sealed and stirred at 70° C. for 3 h. LCMS showed the desired product. The reaction was cooled to room temperature and poured very slowly and carefully into _{saturated NaHCO 3 solution.} The organic layer was then separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 450.0 (M+1).

Step 6: 5-Chloro-3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile

5-Chloro-3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)- in trifluoroacetic acid (58.4 mL) and trifluoroacetic anhydride (19.45 mL)- A flask with a mixture of 6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-fluorobenzonitrile (7 g, 15.56 mmol) was stirred at 80° C. for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and hexanes (100 mL) was added slowly until a white solid formed. After stirring for 30 minutes, a white solid was collected on top of a filter and dried under vacuum to afford the title compound. MS: 330.0 (M+1).

Intermediate AB14

5-Chloro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

Step 1: 3-((4-Acetyl-6-methoxypyrimidin-5-yl)oxy)-5-chloro-2-methylbenzonitrile

To a solution of 1-(5-fluoro-6-methoxypyrimidin-4-yl)ethanone, B08 (2.8 g, 16.46 mmol) in DMF (20 mL) under nitrogen under nitrogen potassium carbonate (6.82 g, 49.4 mmol) and 5-chloro-3-hydroxy-2-methylbenzonitrile, A06 (3.31 g, 19.75 mmol). The resulting mixture was heated at 40° C. for 2 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (20-60% EtOAc/petroleum ether) to give the title compound. MS: 318.4 (M+1).

Step 2: 5-Chloro-3-((4-(1-hydroxyethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile

To a stirred solution of 3-((4-acetyl-6-methoxypyrimidin-5-yl)oxy)-5-chloro-2-methylbenzonitrile (1.8 g, 5.67 mmol) in methanol (50 mL) cerium chloride (iii) Heptahydrate (3.17 g, 8.50 mmol) was added followed by slow addition of sodium borohydride (0.214 g, 5.67 mmol). The resulting suspension was allowed to stir at 0° C. for 1 h, then quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (40-80% EtOAc/petroleum ether) to afford the title compound. MS: 320.0 (M+1).

Step 3: 5-Chloro-3-((4-(1-fluoroethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-Chloro-3-((4-(1-hydroxyethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile (1.4 g, 4.38 mmol) in DCM (5 mL) Deoxofluor (1.615 mL, 8.76 mmol) was added to a stirred solution of The resulting mixture was allowed to warm to room temperature for 3 hours, then diluted with DCM _{and washed with saturated aqueous NaHCO 3} solution and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 40% EtOAc/petroleum ether) to give the title compound. MS: 322.4 (M+1).

Step 4: 5-Chloro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-Chloro-3-((4-(1-fluoroethyl)-6-methoxypyrimidin-5-yl)oxy)-2-methylbenzonitrile (1.2 g, 3.73 mmol) in ACN (20 mL) To a stirred solution of sodium iodide (1.118 g, 7.46 mmol) and TMS-Cl (0.953 ml, 7.46 mmol) under nitrogen were added. The resulting mixture was heated at 80° C. for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica (40-80% EtOAc/petroleum ether) to afford the title compound. MS: 306.4 (M-1).

Intermediate AB15

5-Chloro-2-methyl-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-Chloro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)- 2-methylbenzonitrile

5-Fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one, B18 (9.0 g, 29.8 mmol), 5- in DMF (60 mL) To a solution of chloro-3-hydroxy-2-methylbenzonitrile, A06 (4.99 g, 29.8 mmol) was added potassium carbonate (8.23 g, 59.6 mmol). The reaction mixture was stirred at 100° C. for 16 h, then diluted with water (85 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-35% EtOAc/petroleum-ether) to give the title compound. MS: 450.8 (M+1).

Step 2: 5-Chloro-2-methyl-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyri in ACN (70 mL) and water (5 mL) To a solution of midin-5-yl)oxy)-2-methylbenzonitrile (3 g, 6.67 mmol) was added cerium ammonium nitrate (18.28 g, 33.3 mmol). The reaction mixture was stirred at room temperature for 24 h, then diluted with water (10 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (70 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-35% EtOAc/petroleum ether) to give the title compound. MS: 328.0 (M-1).

Intermediate AB16

5-Chloro-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-(3-Bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

To a solution of 5-fluoro-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one, B18 (1 g, 3.31 mmol) in DMF (10 mL) At 25° C. 3-bromo-5-chloro-2-fluorophenol, A04 (0.821 g, 3.64 mmol) and K ₂ CO ₃ (16.54 mg, 0.120 mmol) were added. The reaction mixture was stirred at 80° C. for 1 h, then diluted with water (3 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC plate (25% EtOAc/petroleum ether) to afford the title compound. MS: 507.2 (M+1). ¹ H NMR (400 MHz, chloroform-d) δ = 8.03 (d, J=4.4 Hz, 1H), 7.34-7.24 (m, 3H), 7.04-6.89 (m, 2H), 6.86 (dd, J=2.4, 6.6 Hz, 1H), 5.07 (s, 2H), 3.81 (s, 3H).

Step 2: 5-Chloro-2-fluoro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine-5- yl) oxy) benzonitrile

5-(3-Bromo-5-chloro-2-fluorophenoxy)-3-(4-methoxybenzyl)-6-(trifluoromethyl)pyrimidine-4 (3H) in NMP (3 mL) A stirred solution of a mixture of )-one (300 mg, 0.591 mmol) and copper(I) cyanide (265 mg, 2.95 mmol) was stirred at 170° C. for 7 h, then diluted with water (30 mL), followed by EtOAc (3x5 mL). The solid precipitate was washed with mixed solvent DCM:MeOH:MeCN=1:1:1 (5 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC plate (50% EtOAc/petroleum ether) to afford the title compound. ¹ H NMR (400 MHz, chloroform-d) δ= 8.17 (s, 1H), 7.35-7.30 (m, 1H), 7.25 (d, J=8.7 Hz, 2H), 7.14 (dd, J=2.4, 7.0 Hz) , 1H), 6.98-6.86 (m, 2H), 5.06 (s, 2H), 3.79 (s, 3H).

Step 3: 5-Chloro-2-fluoro-3-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((1-(4-methoxybenzyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine in TFA (2 mL) To a solution of-5-yl)oxy)benzonitrile (200 mg, 0.176 mmol) was added TFAA (1 mL). The resulting mixture was stirred at 110° C. for 2 h, then _{quenched by the addition of a saturated aqueous solution of NaHCO 3} (5 mL), and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step. MS: 375.0 (M+ACN+1).

Intermediate AB17

3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile

Step 1: 3-Chloro-5-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl )oxy)benzonitrile

Compound 5-bromo-6-(1,1-difluoroethyl)-3-(4-methoxybenzyl)pyrimidin-4(3H)-one, B20 (20 g, 55.7) in NMP (140 mL) mmol), 3-chloro-5-hydroxybenzonitrile, A10 (17.10 g, 111 mmol) was added K ₂ CO ₃ (15.39 g, 111 mmol). The resulting mixture was stirred at 140° C. for 24 h. To the mixture was added 3-chloro-5-hydroxy benzonitrile (17.10 g, 111 mmol). The resulting mixture was stirred at 140° C. for a further 16 h, then diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (6.25-50% EtOAc/petroleum ether) to afford the title compound. MS: 432.1 (M+1).

Step 2: 3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)- 5-methylbenzonitrile

3-chloro-5-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6- in water (5.79 mL) and 1,4-dioxane (17.4 mL) Oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (1.0 g, 2.316 mmol), chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2 -Aminobiphenyl)]palladium(II) (155 mg, 0.232 mmol), potassium methyltrifluoroborate (424 mg, 3.47 mmol) and _{a mixture of Cs 2} CO ₃ (2264 mg, 6.95 mmol)) with N ₂ After purging, it was heated to 130°C. After 30 minutes, the mixture was passed through a Celite® filter bed. The filtrate was diluted with EtOAc (10 mL) and washed with water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-70% EtOAc/hexanes) to give the title compound. MS: 412.1 (M+1). ¹ H NMR (600 MHz, chloroform-d) δ 8.13 (s, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.17 (s, 1H), 7.01 (s, 1H), 6.89 (d, J) = 8.6 Hz, 3H), 5.05 (s, 2H), 3.80 (s, 3H), 2.35 (s, 3H), 1.93 (t, J = 18.8 Hz, 3H).

Step 3: 3-((4-(1,1-difluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)-5-methylbenzonitrile

3-((4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy in TFA (9297 μL) )-5-Methylbenzonitrile (841.5 mg, 2.045 mmol) was added anisole (223 uL, 2.045 mmol) and TFAA (930 μL). The resulting mixture was heated to 110° C. for 15 min and concentrated under reduced pressure. The residue was taken up in DCM (20 mL), _{washed with saturated aqueous NaHCO 3} solution (2x5 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-10% MeOH/DCM) to give the title compound. MS: 292.1 (M+1). ¹ H NMR (600 MHz, chloroform-d) δ 8.08 (s, 1H), 7.20 (s, 1H), 7.02 (s, 1H), 6.93 (s, 1H), 2.38 (s, 3H), 1.96 (t) , J = 18.8 Hz, 3H).

Intermediate BC section

Intermediate BC01

5-fluoro-3-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidine-4(3H )-On

5-fluoro-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4(3H)-one, B01 (48 mg, 0.224 mmol), lithium bromide (19.47) in DMF (2242 μL) mg, 0.224 mmol) and K ₂ CO ₃ (77 mg, 0.561 mmol) was added 3-(chloromethyl)-2-methoxy-4,6-dimethylpyridine, C16 (41.6 mg, 0.224 mmol) . The resulting mixture was heated to 50° C. overnight, then filtered and purified using reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 363.9 (M+1). ¹ H NMR (500 MHz, chloroform-d) δ 8.18 (s, 1H), 6.65 (s, 1H), 5.08 (s, 2H), 3.94 (s, 3H), 2.46 (s, 3H), 2.40 (s) , 3H).

The following intermediates in Table 7 were prepared using the corresponding intermediates B and C under conditions analogous to the above synthetic procedures outlined in synthetic intermediate BC01.

Table 7

Intermediate BC04

5-Fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

5-Fluoro-6-(trifluoromethyl)pyrimidin-4(3H)-one, B04 (0.207 g, 1.139 mmol) and 3-(chloromethyl)-5-fluoro in NMP (5.70 mL) at room temperature To a stirred solution of rho-2-methoxypyridine, C20 (0.2 g, 1.139 mmol) was added potassium carbonate (0.315 g, 2.278 mmol). The resulting mixture was stirred at room temperature overnight and diluted with water (3 mL) and EtOAc (3 mL). The organic layer was separated and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 322.1 (M+1).

The following intermediates in Table 8 were prepared using the corresponding intermediates B and C under conditions analogous to the above synthetic procedures outlined in synthetic intermediate BC04.

Table 8

Example 1

5-Chloro-2-fluoro-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-Chloro-2-fluoro-3-((1-((2-methoxy-6-(methoxymethyl)pyridin-3-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

3-(chloromethyl)-2-methoxy-6-(methoxymethyl)pyridine, C15 (30 mg, 0.149 mmol), 5-chloro-2-fluoro-3-((6) in DMF (1 mL) K in a stirred solution of -oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile AB04 (35 mg, 0.086 mmol) ₂ CO ₃ (23.81 mg, 0.172 mmol) and lithium bromide (11.22 mg, 0.129 mmol) were added. The resulting mixture was stirred at 15° C. for 1 hour. TLC showed the reaction was complete, the mixture _{was diluted with H 2} O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC plate (50% EtOAc/petroleum ether) to afford the title compound. MS: 531 (M+1).

Step 2: 5-Chloro-2-fluoro-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo -4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((1-((2-methoxy-6-(methoxymethyl)pyridin-3-yl)methyl)-6-oxo-4- in ACN (0.5 mL) To a stirred solution of (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy) benzonitrile (25 mg, 0.047 mmol) _{under N 2} KI (23.45 mg , 0.141 mmol) and TMS-Cl (0.018 ml, 0.141 mmol) were added. The resulting mixture was stirred at 70° C. for 1 hour. TLC showed the reaction was complete. The mixture was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 517 (M+1). ¹ H NMR (400 MHz, CDCl3): δ9.79 (s, 1 H) 8.78 (s, 1 H) 7.69 (d, J=6.84 Hz, 1 H) 7.31 (m, J=4.41, 2.43 Hz, 1 H) 7.07 (dd, J=6.84, 2.43 Hz, 1 H) 6.15 - 6.45 (m, 1 H) 6.10 (d, J=6.84 Hz, 1 H) 4.94 (s, 2 H) 4.36 (s, 2 H) ) 3.45 (s, 3 H).

The following examples in Table 9 were prepared in a manner analogous to that described above for the synthesis of Example 1 using the appropriate Intermediate AB and Intermediate C.

Table 9

Example 14

5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

Step 1: 5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-di in NMP (795 μL) at room temperature Stirring of hydropyrimidin-5-yl)oxy)benzonitrile, AB01 (30 mg, 0.080 mmol) and 3-(chloromethyl)-5-fluoro-2-methoxypyridine, C20 (15.36 mg, 0.087 mmol) To the solution was added potassium carbonate (21.98 mg, 0.159 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (3 mL) and extracted with EtOAc (3 mL). The organic layer was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS: 517.1 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-(difluoromethyl)-3-((1-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1) in ACN (775 μL) To a solution of ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (40 mg, 0.077 mmol) TMS-I (10.54 μL, 0.077 mmol) was added dropwise at room temperature. After addition, the resulting mixture was heated to 60° C. for 1 h, then diluted with EtOAc (2 mL), saturated aqueous NaHCO ₃ solution (1 mL) and saturated aqueous Na ₂ S ₂ O ₃ solution (1 mL) was quenched with The organic layer was separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 503.1 (M+1). ¹ H NMR (600 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.73 (s, 1H), 7.61 - 7.56 (m, 2H), 7.31 (s, 1H), 6.94 (d, J = 16.0 Hz) , 1H), 6.86 (s, 1H), 6.77 (s, 1H), 4.87 (s, 2H), 2.47 (s, 3H).

The following examples in Table 10 were prepared in a manner analogous to that described above for the synthesis of Example 14, using the appropriate Intermediate AB and Intermediate C.

Table 10

Example 21

5-Chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(perfluoro ethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-Chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)- 1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB06 in DCM (1303 μL) To an ice-cold solution of (50 mg, 0.130 mmol) and (2-methoxy-6-methylpyridin-3-yl)methanol, C17 (20.0 mg, 0.13 mmol) was added DIAD (25.3 μL, 0.130 mmol) dropwise. The resulting mixture was allowed to warm to room temperature, then _{diluted with saturated aqueous NaHCO 3} solution and extracted with DCM. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 519.1 (M+1).

Step 2: 5-Chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-( perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl) in ACN (752 μL) )-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (39 mg, 0.075 mmol) and potassium iodide (37.4 mg, 0.226 mmol) in a solution of TMS-Cl (28.8 μl, 0.226 mmol) ) was added. The resulting mixture was heated to 50° C. for 1 h, then cooled to room temperature, diluted with MeOH (1 mL) and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 505.0 (M+1). ¹ H NMR (500 MHz, chloroform-d) δ 8.78 (s, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.33 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 6.12 (d, J = 7.5 Hz, 1H), 4.94 (s, 2H), 2.36 (s, 3H).

Example 22 below in Table 11 was prepared in a manner analogous to that described above for the synthesis of Example 21 using the appropriate Intermediate AB and Intermediate C.

Table 11

Example 23

5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(perfluoro ethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-(difluoromethyl)-3-((1-((2-methoxypyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6- dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy in THF (633 μL)) To a solution of benzonitrile, AB03 (50 mg, 0.127 mmol) was added (2-methoxypyridin-3-yl)methanol, C18 (19.36 mg, 0.139 mmol) and triphenylphosphine (127 mg, 0.380 mmol) Then (E)-di-tert-butyl diazene-1,2-dicarboxylate (64.1 mg, 0.278 mmol) was added. The resulting mixture was stirred overnight, filtered and concentrated under reduced pressure to afford the title compound. MS: 517.1 (M+1).

Step 2: 5-(difluoromethyl)-2-methyl-3-((6-oxo-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-( perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-(difluoromethyl)-3-((1-((2-methoxypyridin-3-yl)methyl)-6-oxo-4-(perfluoroethyl)-1 in DMA (629 μL), To a solution of 6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (65 mg, 0.126 mmol) was added pyridine hydrochloride (43.6 mg, 0.378 mmol). The resulting mixture was stirred at 120° C. for 60 min and then purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 503.1 (M+1). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 8.77 (s, 1H), 7.73 (s, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.37 (s, 2H), 6.12 (t, J = 6.7 Hz, 1H), 4.85 (s, 2H), 2.44 (s, 3H).

Example 24

3-((1-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoro Roethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

Step 1: 5-Chloro-3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetra) Fluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

5-Chloro-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5- in DMF (3 mL) A stirred solution of yl)oxy)benzonitrile, AB09 (90 mg, 0.249 mmol) and 3-(chloromethyl)-2-methoxy-4,6-dimethylpyridine, C16 (46.2 mg, 0.249 mmol) followed by potassium carbonate (68.8 mg, 0.498 mmol) was added. The resulting mixture was stirred at room temperature for 5 h, then diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (0-60% EtOAc/PE) to afford the title compound. MS: 510.8 (M+1).

Step 2: 3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

5-chloro-3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2, To a stirred solution of 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile (70 mg, 0.137 mmol) cesium carbonate (134 mg, 0.411 mmol) and PdCl ₂ (dppf) (22.38 mg, 0.027 mmol) and trimethylboroxine (25.8 mg, 0.206 mmol) were added. The resulting mixture was heated to 100° C. overnight, then quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (0-40% EtOAc/PE) to afford the title compound. MS: 490.8 (M+1).

Step 3: 3-((1-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) -1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile

3-((1-((2-methoxy-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoro) in ACN (3 mL) To a stirred ice-cooled solution of roethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2,5-dimethylbenzonitrile (60 mg, 0.122 mmol) sodium iodide (36.7 mg, 0.245 mmol) and TMS-Cl (0.031 ml, 0.245 mmol) were added. The resulting mixture was heated to 80° C. for 1 h, then quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 477.2 (M+1).

Example 25

5-(difluoromethyl)-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

Step 1: 3-((1-((6-chloro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-Dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile

6-Chloro-3-(chloromethyl)-2-methoxypyridine, C13 (244 mg, 1.272 mmol) and 5-(difluoromethyl)-2-methyl-3-(( A stirred solution of 6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB01 (480 mg, 1.272 mmol) To K ₂ CO ₃ (352 mg, 2.54 mmol) was added. The resulting mixture was stirred at 25° C. overnight, then diluted with water (50 mL) and stirred at room temperature for 30 min. The precipitate was collected on top of the filter, washed with water (3x) and then air-dried to afford the title compound. MS: 533.3 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo -4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

3-((1-((6-chloro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2) in 1,4-dioxane (1 mL) -tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (20 mg, 0.038 mmol), potassium trifluoro ( 2 M aqueous solution of cesium carbonate in _{an N 2} purged mixture of (4-methoxybenzyl)oxy)methyl)borate (14.53 mg, 0.056 mmol) and cataCXium® A Pd G2 (5.02 mg, 7.51 μmol) (0.5 mL, 1.0 mmol) was added. The resulting mixture was heated in a microwave oven at 150° C. for 15 min and then extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was taken up with ACN (1 mL) and treated with KI (6.23 mg, 0.038 mmol), and TMS-Cl (40 μl, 0.313 mmol). The resulting mixture was heated in a microwave oven at 100° C. for 10 minutes and then purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 515.2 (M+1).

The following examples in Table 12 were prepared in a manner analogous to that described above for the synthesis of Example 25 using the intermediate of Step 1 in the synthesis of Example 25 and using the appropriate heteroaryl or alkyl boronate in the second column. .

Table 12

Example 29

5-(difluoromethyl)-3-((1-((6-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)- 6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

Step 1: 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-Dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile

3-((1-((6-chloro-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) in tall (1877 μL) -1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (intermediate from step 1 of Example 25) (100 mg, 0.188 mmol), A mixture of bis(triphenylphosphine) palladium(II) dichloride (26.3 mg, 0.038 mmol), and tributyl(1-ethoxyvinyl)tin (127 μL, 0.375 mmol) was stirred at 100° C. overnight, followed by EtOAc and saturated aqueous KF solution and treated with concentrated HCl (1 mL). The mixture was stirred at room temperature overnight and passed through Celite® in a funnel. The filtrate was extracted with EtOAc (2X). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 541.4 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((6-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl) methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetra) in THF (278 μL) at -78°C To a solution of fluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (30 mg, 0.056 mmol) in Et ₂ O A 3 M solution of magnesium bromide (37.0 μL, 0.111 mmol) was added dropwise. When LCMS showed complete conversion, the mixture was quenched with MeOH and water, then partitioned between _{EtOAc and saturated aqueous NaHCO 3 solution.} The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was taken up with ACN (2 mL) and treated with KI (9.22 mg, 0.056 mmol) and TMS-Cl (20 μL, 0.156 mmol). The resulting mixture was heated in a microwave oven at 100° C. for 10 minutes. The mixture was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 543.4 (M+1). ¹ H NMR (600 MHz, acetone-d6) δ 8.77 (s, 1H), 7.67 - 7.54 (m, 2H), 7.22 (s, 1H), 6.77 (d, J = 11.9 Hz, 1H), 6.70 - 6.65 (m, 1H), 6.26 (d, J = 7.2 Hz, 1H), 4.94 (s, 2H), 2.03 (s, 3H), 1.62 (s, 1H), 1.53 (s, 6H).

Example 30

3-Chloro-5-((6-oxo-1-((2-oxo-6-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)methyl)-4- (trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 3-((1-((6-bromo-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)-5-chlorobenzonitrile

3-chloro-5-((6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (2.27 g, 7.19 mmol) in toluene (30 mL) ) in (6-bromo-2-methoxypyridin-3-yl)methanol C02 (1.3 g, 5.96 mmol), triphenylphosphine (3.15 g, 12.01 mmol) and DIAD (2.337 ml, 12.02 mmol) ) was added. The resulting mixture was stirred at room temperature overnight and then diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (30% EtOAc/PE) to give the title compound.

Step 2: 3-((1-((6-Bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1, 6-dihydropyrimidin-5-yl)oxy)-5-chlorobenzonitrile

3-((1-((6-bromo-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-di in ACN (20 mL) To a stirred solution of hydropyrimidin-5-yl)oxy)-5-chlorobenzonitrile (1.8 g, 3.49 mmol) was added sodium iodide (1.046 g, 6.98 mmol) and TMS-Cl (0.892 ml, 6.98 mmol) added. The reaction mixture was stirred at 80° C. overnight, then cooled to room temperature, added some more ACN, stirred and filtered. The filter cake was washed with ACN. The filtrate was concentrated under reduced pressure to give the title compound. MS: 501.2 and 503.2 (M+1).

Step 3: 3-Chloro-5-((6-oxo-1-((2-oxo-6-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)methyl) -4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

3-((1-((6-bromo-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6 in 1,4-dioxane (53.2 μL) and water (26.6 μL) -oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-5-chlorobenzonitrile (20 mg, 0.040 mmol), 4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.28 mg, 0.048 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (3.26 mg, 3.99) μmol), potassium phosphate tribasic (22.85 mg, 0.108 mmol) was degassed and purged with _{N 2 .} The resulting mixture was stirred at 80° C. for 3 hours. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure. The residue was subjected to reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 489.0 (M+1).

Example 31

5-Chloro-2-fluoro-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4- (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-Chloro-2-fluoro-3-((1-((2-methoxy-6-vinylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5 in DMF (2 mL) -yl)oxy)benzonitrile AB04 (150 mg, 0.410 mmol) and K ₂ CO ₃ (283 mg, 2.051 mmol) in a solution of 3-(chloromethyl)-2-methoxy-6-vinylpyridine, C19 (75 mg, 0.410 mmol) and lithium bromide (42.8 mg, 0.492 mmol). The resulting mixture was stirred at 20° C. for 20 h, then _{quenched with H 2} O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC plate (25% EtOAc/PE) to afford the title compound. MS: 513.1 (M+1).

Step 2: 5-Chloro-2-fluoro-3-((1-((6-formyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2) ,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-chloro-2-fluoro-3-((1-((2-methoxy-6-vinylpyridin-3-yl) in 1,4-dioxane (3 mL) and H _{2 O (1 mL))} methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (80 mg, 0.156 mmol) and 2 To a mixture of ,6-lutidine (0.051 mL, 0.438 mmol) was added osmium tetroxide (1.224 μL, 3.90 μmol) dissolved in t-BuOH (0.1 mL). The resulting mixture was stirred at 20° C. for 30 min, and to the mixture was added sodium periodate (122 mg, 0.571 mmol). The resulting mixture was stirred at 20° C. for 1.5 h, then diluted with EtOAc (10 mL) and carefully poured into water (10 mL). The organic layer was _{washed with saturated aqueous Na 2} S ₂ O ₃ (10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford the title compound. MS: 515.1 (M+1).

Step 3: 5-Chloro-2-fluoro-3-((1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-chloro-2-fluoro-3-((1-((6-formyl-2-methoxypyridin-3-yl)methyl)-6-oxo in EtOAc (1 mL) and MeOH (3 mL) _{Zn(BH 4} ) in a solution of -4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (70 mg, 0.136 mmol) ₂ (0.136 ml, 0.136 mmol) was added. The resulting mixture was stirred at 20° C. for 0.25 h, then quenched with 1N HCl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step. MS: 517.1 (M+1).

Step 4: 5-Chloro-2-fluoro-3-((1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo -4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo-4- in ACN (3.00 mL) KI (57.8 mg, 0.348 mmol) in a solution of (1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (60 mg, 0.116 mmol) and TMS-Cl (0.045 ml, 0.348 mmol) were added. The resulting mixture was stirred at 70° C. for 1 hour and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 503.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ11.75 (s, 1H), 8.79 (s, 1H), 7.86-7.84 (m, 1 H), 7.69-7.50 (m, 1H), 7.48- 7.46 (d, 1H), 6.87-6.74 (m, 1H), 6.17-6.15 (m, 1 H), 5.42 (s, 1H), 4.86 (s, 2H), 4.27 (s, 2H).

Examples 32 (isomer A) and 33 (isomer B)

(S)-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine) -3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, and (R)-5-chloro-2-fluoro-3-((4- (1-Fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-1,6-dihydropyri midin-5-yl)oxy)benzonitrile

Step 1: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((2-methoxy-6-vinylpyridin-3-yl)methyl)-6-oxo -1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile in DMF (5 mL) , in a solution of AB12 (0.3 g, 0.963 mmol) 3-(chloromethyl)-2-methoxy-6-vinylpyridine, C19 (0.177 g, 0.963 mmol), K ₂ CO ₃ (0.399 g, 2.89 mmol) and Lithium bromide (0.167 g, 1.925 mmol) was added. The resulting mixture was stirred at 20 °C for 1 h, then extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was triturated with MeOH to give the title compound, which was used directly without further purification.

Step 2: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-formyl-2-methoxypyridin-3-yl)methyl)-6- Oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((2-methoxy-6) in 1,4-dioxane (1.5 mL) and water (0.5 mL) -vinylpyridin-3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (200 mg, 0.436 mmol) in a mixture of 2,6-dimethylpyridine (131) mg, 1.220 mmol) and a solution of osmium tetroxide (0.1 mL, 0.436 mmol) in t-BuOH (0.1 mL). The resulting mixture was stirred at 20 °C for 15 min. Then sodium periodate (336 mg, 1.569 mmol) was added. The reaction was stirred at 20° C. for 1.5 h, then diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica (0-20% EtOAc/petroleum ether) to give the title compound. MS: 461.1 (M+1).

Step 3: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl)methyl) -6-Oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-formyl-2-methoxypyridine-) in THF (3 mL) and EtOAc (2 mL) To a solution of 3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (55 mg, 0.107 mmol) 1M Zn(BH ₄ ) ₂ solution in THF (0.021 mL, 0.021 mmol) was added at -30°C. The resulting mixture was stirred at -30 °C for 0.5 h. The reaction was quenched with water (1 drop) and then concentrated under reduced pressure to afford the title compound. MS: 463.1 (M+1).

Step 4: 5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine- 3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; (S)-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine) -3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; and (R)-5-chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-oxo-1,2-dihydro pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((4-(1-fluoroethyl)-1-((6-(hydroxymethyl)-2-methoxypyridin-3-yl) in ACN (3 mL) ) In a solution of methyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (49 mg, 0.106 mmol) KI (22.14 mg, 0.133 mmol) and TMS-Cl (0.044 ml) , 0.347 mmol) was added. The resulting mixture was stirred at 70° C. for 5 h and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the racemic title compound. MS: 449 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.27 (br d, J=4.63 Hz, 2 H) 4.83 (s, 2 H) 5.46 (s, 1 H) 5.63 - 5.88 (m, 1 H) 6.15 (br d, J=7.28 Hz, 1 H) 7.42 (d, J=7.06 Hz, 1 H) 7.58 (br d, J=5.73 Hz, 1 H) 7.82 (br s, 1 H) 8.68 (s, 1 H). The racemic mixture was purified by chiral SFC (Chiralpak IC-H column, 250 x30 mm id, 5 μm, IPA/CO ₂ =35%) to obtain Example 32 Isomer A (faster elution) and Example 33 Isomer B ( slower elution).

Example 34 (Isomer A)

(S) or (R)-5-chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-oxo-1,2-dihydropyridin-3-yl )methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1 ,6-Dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile

5-Chloro-2-fluoro-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine-5 in DMF (4 mL) 1-(5-(chloromethyl)-6-methoxypyridin-2-yl)ethanone, C21 (135 mg, 0.676 mmol) in a solution of -yl)oxy)benzonitrile, AB04 (247 mg, 0.676 mmol) and K ₂ CO ₃ (187 mg, 1.352 mmol) and lithium bromide (88 mg, 1.014 mmol) were added. The resulting mixture was stirred at 30° C. for 5 h _{, diluted with H 2} O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (50% EtOAc/PE) to give the title compound. MS: 529.2 (M+1).

Step 2: 5-Chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo-4-( 1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

3-((1-((6-acetyl-2-methoxypyridin-3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl) in EtOAc (21 mL) In a solution of )-1,6-dihydropyrimidin-5-yl)oxy)-5-chloro-2-fluorobenzonitrile (144 mg, 0.272 mmol) 1M Zn(BH ₄ ) _{2 in THF at 20° C.} solution (0.272 ml, 0.272 mmol) was added. The resulting solution was stirred at 15-20° C. for 0.5 h, then quenched with 4N aqueous HCl solution (5 _{mL), diluted with H 2} O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound. MS: 531.2 (M+1).

Step 3: (S) or (R)-5-chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-oxo-1,2-dihydropyridine- 3-yl)methyl)-6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((1-((6-(1-hydroxyethyl)-2-methoxypyridin-3-yl)methyl)-6-oxo- in ACN (32 mL) To a solution of 4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (185 mg, 0.349 mmol) KI (174 mg, 1.046) mmol), and TMS-Cl (0.134 ml, 1.046 mmol). The resulting mixture was stirred at 70° C. for 2 h, then diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the racemic title compound. The racemic mixture was purified by chiral SFC (Chiralpak AD-H column, 250 x30 mm id, 5 μm, 25% IPA/CO ₂ , containing 0.1% NH ₄ OH as modifier) in Example 34 (isomer A, faster eluted) was obtained. MS: 517.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (d, J = 6.58 Hz, 3 H) 4.49 (br d, J = 4.39 Hz, 1 H) 4.86 (s, 2 H) 5.49 (br d , J =3.51 Hz, 1 H) 6.17 (d, J = 7.45 Hz, 1 H) 6.68 - 7.07 (m, 1 H) 7.47 (d, J = 7.02 Hz, 1 H) 7.76 (dd, J=7.24, 2.41 Hz, 1 H) 7.85 (dd, J=4.38, 2.63 Hz, 1 H) 8.80 (s, 1 H).

Example 35

3-(difluoromethyl)-5-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(trifluoro Rhomethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Potassium carbonate (34.4 mg, 0.249 mmol) was dissolved in DMF (623 μL) at room temperature with 5-fluoro-3-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-(trifluoro To a stirred solution of methyl)pyrimidin-4(3H)-one, BC04 (40 mg, 0.125 mmol) and 3-(difluoromethyl)-5-hydroxybenzonitrile, A01 (25.3 mg, 0.149 mmol) did The resulting mixture was stirred at 100° C. overnight, then diluted with water (2 mL) and EtOAc (2 mL). The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ACN (2 mL) and TMS-I (85 μL, 0.623 mmol) was added dropwise at room temperature. After addition, the resulting mixture was heated to 60° C. for 2 h. The reaction was diluted with EtOAc (2 mL) and quenched with saturated aqueous NaHCO ₃ solution (1 mL) and saturated aqueous Na ₂ S ₂ O ₃ (1 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 457.1 (M+1). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.62-7.55 (m, 2H), 7.00 (t, J= 55.2 Hz, 1H), 4.88 (s, 2H).

The following examples in Table 13 were prepared in a manner analogous to that described above for the synthesis of Example 35, using the appropriate Intermediate A and Intermediate BC.

Table 13

Example 39

5-Chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(1,1 ,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

Step 1: 5-Chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(1,1,2, 2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Fluoro-3-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-(1,1,2,2-tetrafluoroethyl)pyrimidine- in DMF (859 μL) 4(3H)-one, BC03 (60 mg, 0.172 mmol), 5-chloro-2-fluoro-3-hydroxybenzonitrile, A05 (30.9 mg, 0.180 mmol), potassium carbonate (47.5 mg, 0.344 mmol) The mixture of was heated to 80 °C overnight, then at 100 °C for a second night. The crude material was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 501.2 (M+1).

Step 2: 5-Chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-( 1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

5-Chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(1,1) in ACN (230 μL) TMS in a solution of 2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile (11.5 mg, 0.023 mmol) and potassium iodide (11.44 mg, 0.069 mmol) -Cl (8.80 μL, 0.069 mmol) was added. The resulting mixture was heated to 50° C. for 4 h, then quenched with MeOH (1 mL). The crude material was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 487.2 (M+1).

The following examples in Table 14 were prepared in a manner analogous to that described above for the synthesis of Example 39, using the appropriate Intermediate A and Intermediate BC.

Table 14

Example 42

5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-(tri Fluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

Step 1: 3-((1-((2-chloro-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidine -5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile

5-(difluoromethyl)-3-hydroxy-2-methylbenzonitrile, A02 (118 mg, 0.643 mmol) in DMF (2 mL), ((2-chloro-4,6-dimethylpyridine-3- A mixture of yl)methyl)-5-fluoro-6-(trifluoromethyl)pyrimidin-4(3H)-one, BC02 (180 mg, 0.536 mmol), potassium carbonate (148 mg, 1.072 mmol) in 80 Stir at °C for 15 h and pass through a filter. The filter cake was washed with EtOAc (10 mL). The filtrate was partitioned between EtOAc and water. The layers were separated. And the aqueous layer was further extracted with EtOAc (3x10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc/hexanes) to give the title compound. MS: 499.1 (M+1).

Step 2: 5-(difluoromethyl)-3-((1-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4 -(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

3-((1-((2-chloro-4,6-dimethylpyridin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1 in AcOH (32.100 mL, 561 mmol), A solution of 6-dihydropyrimidin-5-yl)oxy)-5-(difluoromethyl)-2-methylbenzonitrile (140 mg, 0.281 mmol) was heated at 100° C. until LCMS showed complete conversion. Heated for one night. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA as modifier) to isolate the title compound. MS: 481.1 (M+1). ¹ H NMR (500 MHz, chloroform-d) δ 8.77 (s, 1H), 7.45 (s, 1H), 7.26 (d, J = 1.8 Hz, 3H), 6.73 (s, 1H), 6.51 (t, J) = 55.9 Hz, 1H), 6.16 (s, 1H), 5.02 (s, 2H), 2.64 (s, 1H), 2.59 (s, 3H), 2.43 (d, J = 1.4 Hz, 3H), 2.35 (s) , 3H).

Example 43: Determination of cell death (SMACK) activity:

PBMCs derived from healthy donors were treated in complete medium (L-glutamine; 10% heat inactivated fetal bovine serum; RPMI 1640 with 100 U/mL penicillin-streptomycin) containing 5 μg/mL phytohemagglutinin. Grow at 2.5 x 10 ⁶ cells/mL under 5% CO ₂ , 37° C. and 90% humidity for 3 days. On day 4, PHA-stimulated cells were washed and IL-2 (10 U/mL) containing VSV-G pseudotyped HIV virus stock (VSV-G/pNLG1-P2A-ΔEnv - 20 μg/mL p24) the mixture was incubated for about 20 x 10 ⁶ cells to reproduce gae / mL was suspended for four hours under 37 ℃, 5% CO ₂ and 90% humidity in complete medium with. VSV-G/pNLG1-P2A-ΔEnv is a VSV-G pseudotyped virus derived from pNL43 in which egfp is inserted 5' of nef and eGFP expression is derived from a normal spliced RNA transcript. The virus contained a 50 amino acid truncated Vif due to deletion of a single nucleotide causing a frameshift and does not express Nef due to a stop codon after gfp. HIV Env is not expressed due to a frameshift that creates multiple stop codons. The infected cells were then centrifuged at 200×g for 3 minutes at 22° C., washing 3 times with complete medium plus 10 U/mL IL-2. ^{Cells were resuspended at 5×10 6} cells/mL in complete medium plus 10 U/mL IL- ₂ and incubated overnight at 37° C., 5% CO 2 and 90% humidity. ^{For compound treatment, infected PBMCs were treated 4×10 5} by RPMI 1640 containing L-glutamine, 50% normal human serum (NHS), 100 U/mL penicillin-streptomycin plus IL-2 (10 U/mL). Diluted to canine cells/mL and 20,000 cells were transferred to each well in a 384-well poly-D-lysine coated compound plate containing compound, with final DMSO <0.5%. Compounds were tested in 10-point 3-fold titrations. Plates were analyzed on an Acumen ex3 imager using a blue laser 488 nm and the number of GFP positive subjects was collected with loss of GFP indicating death of infected cells. Titration curves and EC ₅₀ values were calculated using a 4-parameter logistic fit. The results are presented in Table 15.

Table 15

Claims (30)

A compound of formula (I) or a pharmaceutically acceptable salt thereof.

here
R ¹ is H, halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or substituted with 1 to 7 F -C _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F;
R ² is CN and R ³ is H; or R ² is H and R ³ is CN;
R ⁴ is -H, halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or substituted with 1 to 7 F -C _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F;
R ⁵ is -H, halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or substituted with 1-7 F -C _{1-3 alkyl, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F;
R ⁶ _{is halo or —C 1-6} alkyl substituted with 1 to 9 —F;
R ⁷ is —H or —C _1-3 alkyl;
R ⁸ is -H, halo or -C _1-3 alkyl;
R ⁹ is —H, pyrazolyl, or —C _1-6 alkyl unsubstituted or substituted with —OH or —OC _{1-3 alkyl.} The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁶ _{is halo, or —C 1-3} alkyl substituted with 1 to 7 —F. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R ⁷ is H or —CH _{3 .} The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein R ^{8 is -H or halo.} 5. The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein R ⁹ is -H, pyrazolyl, or -C _1-4 alkyl unsubstituted or substituted with -OH or -OC _{1-3 alkyl.} 6. A compound according to any one of claims 1 to 5 having structural formula II or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein R ⁴ is halo, -NH ₂ , -NH-C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , -C _3-6 cycloalkyl, unsubstituted or 1 to 7 _{-C 1-3} alkyl substituted with F _{, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F, or a pharmaceutically acceptable salt thereof. 8. The compound or pharmaceutically acceptable salt thereof according to claim 7, wherein R ⁴ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. 8. The compound according to claim 7, wherein R ¹ is -H, or a pharmaceutically acceptable salt thereof. 8. The method of claim 7, wherein R ¹ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, unsubstituted or 1 to 7 _{-C 1-3} alkyl substituted with F _{, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F, or a pharmaceutically acceptable salt thereof. 11. The compound or pharmaceutically acceptable salt thereof according to claim 10, wherein R ¹ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. 6. A compound according to any one of claims 1 to 5 having structural formula III or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein R ¹ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, unsubstituted or 1 to 7 _{-C 1-3} alkyl substituted with F _{, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F, or a pharmaceutically acceptable salt thereof. 14. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R ¹ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. 14. The method of claim 13, wherein R ⁵ is halo, —NH ₂ , —NH—C _1-3 alkyl, —N(C _1-3 alkyl) ₂ , —C _3-6 cycloalkyl, unsubstituted or 1 to 7 _{-C 1-3} alkyl substituted with F _{, or -OC 1-3} alkyl unsubstituted or substituted with 1 to 7 F, or a pharmaceutically acceptable salt thereof. 16. The compound or pharmaceutically acceptable salt thereof according to claim 15, wherein R ⁵ _{is halo, or —C 1-3} alkyl unsubstituted or substituted with 1 to 7 F. The compound according to claim 1, wherein: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19. The method of claim 18, wherein an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV A pharmaceutical composition further comprising an integrase inhibitor, an HIV fusion inhibitor, an HIV entry inhibitor, and an HIV maturation inhibitor. A method comprising administering to a human subject in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of infection by HIV, or the treatment, prevention or delay of the onset or progression of AIDS or ARC. A method for treating infection by HIV, or for treating, preventing, or delaying the onset or progression of AIDS or ARC in said human subject. In an HIV-infected cell in a human subject comprising administering to the subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof A method for deriving GAG-POL dimerization. Selectively killing HIV-infected GAG-POL expressing cells without accompanying cytotoxicity to HIV naive cells in a human subject, comprising administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof how to do it. 23. The method of any one of claims 20-22, wherein the human subject is administered an effective amount of a nucleoside HIV reverse transcriptase inhibitor, a nucleotide HIV reverse transcriptase inhibitor, a nucleoside reverse transcriptase translocation inhibitor, a non-nucleoside A method further comprising administering at least one additional compatible HIV antiviral agent selected from a cleoside HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV fusion inhibitor, an HIV entry inhibitor, and an HIV maturation inhibitor. An HIV virus in a human subject, wherein the viremia is being suppressed by administration of one or more compatible HIV antiviral agents, further comprising administering to the human subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. A method of increasing the inhibition of hematuria. 18. A compound according to any one of claims 1 to 17, for use in a method of treating infection by HIV, or treating, preventing or delaying the onset or progression of AIDS or ARC in a human subject, or a pharmaceutically acceptable compound thereof. salt. 18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable compound thereof, for use in selectively killing HIV infected GAG-POL expressing cells in a human subject without accompanying cytotoxicity to HIV naive cells. salt to be. 18. The compound or pharmaceutical thereof according to any one of claims 1 to 17, for use in enhancing the inhibition of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents. phase-acceptable salts. 18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of infection by HIV, or for the treatment, prevention or delay of the onset or progression of AIDS or ARC in a human subject. use of the salt. 18. A compound according to any one of claims 1 to 17 or a pharmaceutical thereof in the manufacture of a medicament for selectively killing HIV infected GAG-POL expressing cells in a human subject without accompanying cytotoxicity to HIV naive cells. Uses of phase-acceptable salts. 18. A compound according to any one of claims 1 to 17, or a pharmaceutical thereof, for the manufacture of a medicament for enhancing the inhibition of HIV viremia in a human subject whose viremia is being suppressed by at least one compatible HIV antiviral agent. Uses of phase-acceptable salts.